Ortho-sulfonamido bicyclic hydroxamic acids as matrix metalloproteinase and TACE inhibitors

ABSTRACT

This invention provides, low molecular weight, non-peptide inhibitors of matrix metalloproteinases and TNF-α converting enzyme (TACE, tumor necrosis factor-α converting enzyme) of formula: 
     
       
         B 
       
     
     wherein B is                    
     P and Q are                    
     provided that when 
     P is                    
     Q is                    
     and vice versa; 
     or a pharmaceutically acceptable salt thereof.

This application is a continuation-in-part of U.S. patent applicationSer. No. 09/055,856 now abandoned; attorney docket number 33,194-1-C1),filed on Apr. 6, 1998, which is a continuation in part of U.S. patentapplication Ser. No. 08/944,188 filed on Oct. 6, 1997 which claims thebenefit of priority to U.S. Provisional Application No. 60/028,505 filedOct. 16, 1996.

BACKGROUND

The present invention relates to the discovery of novel, low molecularweight, non-peptide inhibitors of matrix metalloproteinases (e.g.gelatinases, stromelysins and collagenases) and TNF-α converting enzyme(TACE, tumor necrosis factor-α converting enzyme) which are useful forthe treatment of diseases in which these enzymes are implicated such asarthritis, tumor metastasis, tissue ulceration, abnormal wound healing,periodontal disease, bone disease, proteinuria, aneurysmal aorticdisease, degenerative cartilage loss following traumatic joint injury,demyelinating diseases of the nervous system and HIV infection.

Matrix metalloproteinases (MMPs) are a group of enzymes that have beenimplicated in the pathological destruction of connective tissue andbasement membranes [Woessner, J. F., Jr. FASEB J. 1991, 5, 2145;Birkedal-Hansen, H.; Moore, W. G. I.; Bodden, M. K.; Windsor, L. J.;Birkedal-Hansen, B.; DeCarlo, A.; Engler, J. A. Crit. Rev. Oral Biol.Med. 1993, 4, 197; Cawston, T. E. Pharmacol. Ther. 1996, 70, 163;Powell, W. C.; Matrisian, L. M. Cur. Top. Microbiol. and Immunol. 1996,213, 1]. These zinc containing endopeptidases consist of several subsetsof enzymes including collagenases, stromelysins and gelatinases. Ofthese classes, the gelatinases have been shown to be the MMPs mostintimately involved with the growth and spread of tumors, while thecollagenases have been associated with the pathogenesis ofosteoarthritis [Howell, D. S.; Pelletier, J.-P. In Arthritis and AlliedConditions; McCarthy, D. J.; Koopman, W. J., Eds.; Lea and Febiger:Philadelphia, 1993; 12th Edition Vol. 2, pp. 1723; Dean, D. D. Sem.Arthritis Rheum. 1991, 20, 2; Crawford, H. C; Matrisian, L. M. InvasionMetast. 1994-95, 14, 234; Ray, J. M.; Stetler-Stevenson, W. G. Exp.Opin. Invest. Drugs, 1996, 5, 323].

It is known that the level of expression of gelatinase is elevated inmalignancies, and that gelatinase can degrade the basement membranewhich may lead to tumor metastasis [Powell, W. C.; Matrisian, L. M. Cur.Top. Microbiol. and Immunol. 1996, 213, 1; Crawford, H. C; Matrisian, L.M. Invasion Metast. 1994-95, 14, 234; Ray, J. M.; Stetler-Stevenson, W.G. Exp. Opin. Invest. Drugs, 1996, 5, 323; Himelstein, B. P.;Canete-Soler, R.; Bernhard, E. J.; Dilks, D. W.; Muschel, R. J. InvasionMetast. 1994-95, 14, 246; Nuovo, G. J.; MacConnell, P. B.; Simsir, A.;Valea, F.; French, D. L. Cancer Res. 1995, 55, 267-275; Walther, M. M.;Levy, A.; Hurley, K.; Venzon, D.; Linehen, W. M.; Stetler-Stevenson, W.J. Urol. 1995, 153 (Suppl. 4), 403A; Tokuraku, M; Sato, H.; Murakami,S.; Okada, Y.; Watanabe, Y.; Seiki, M. Int. J. Cancer, 1995, 64, 355;Himelstein, B.; Hua, J.; Bernhard, E.; Muschel, R. J. Proc. Am. Assoc.Cancer Res. Ann. Meet. 1996, 37, 632; Ueda, Y.; Imai, K.; Tsuchiya, H.;Fujimoto, N.; Nakanishi, I.; Katsuda, S.; Seiki, M.; Okada, Y. Am. J.Pathol. 1996, 148, 611; Gress, T. M.; Mueller-Pillasch, F.; Lerch, M.M.; Friess, H.; Buechler, M.; Adler, G. Int. J. Cancer, 1995, 62, 407;Kawashima, A.; Nakanishi, I.; Tsuchiya, H.; Roessner, A.; Obata, K.;Okada, Y. Virchows Arch., 1994, 424, 547-552.]. Angiogenesis, requiredfor the growth of solid tumors, has also recently been shown to have agelatinase component to its pathology [Crawford, H. C; Matrisian, L. M.Invasion Metast. 1994-95, 14, 234; Ray, J. M.; Stetler-Stevenson, W. G.Exp. Opin. Invest. Drugs, 1996, 5, 323.]. Furthermore, there is evidenceto suggest that gelatinase is involved in plaque rupture associated withatherosclerosis [Dollery, C. M.; McEwan, J. R.; Henney, A. M. Circ. Res.1995, 77, 863; Zempo, N.; Koyama, N.; Kenagy, R. D.; Lea, H. J.; Clowes,A. W. Arterioscler. Thromb. Vasc. Biol. 1996, 16, 28; Lee, R. T.;Schoen, F. J.; Loree, H. M.; Lark, M. W., Libby, P. Arterioscler.Thromb. Vasc. Biol. 1996, 16, 1070.]. Other conditions mediated by MMPsare restenosis, MMP-mediated osteopenias, inflammatory diseases of thecentral nervous system, skin aging, tumor growth, osteoarthritis,rheumatoid arthritis, septic arthritis, corneal ulceration, abnormalwound healing, bone disease, proteinuria, aneurysmal aortic disease,degenerative cartilage loss following traumatic joint injury,demyelinating diseases of the nervous system, cirrhosis of the liver,glomerular disease of the kidney, premature rupture of fetal membranes,inflammatory bowel disease, periodontal disease, age related maculardegeneration, diabetic retinopathy, proliferative vitreoretinopathy,retinopathy of prematurity, ocular inflammation, keratoconus, Sjogren'ssyndrome, myopia, ocular tumors, ocular angiogenesis/neovascularizationand corneal graft rejection.

The hypothesis that MMPs are important mediators of the tissuedestruction that occurs in arthritis has long been considered, since itwas first recognized that these enzymes are capable of degradingcollagens and proteoglycans which are the major structural components ofcartilage [Sapolsky, A. I.; Keiser, H.; Howell, D. S.; Woessner, J. F.,Jr.; J. Clin. Invest. 1976, 58, 1030; Pelletier, J.-P.;Martel-Pelletier, J.; Howell, D. S.; Ghandur-Mnaymneh, L.; Enis, J. E.;Woessner, J. F., Jr., Arthritis Rheum. 1983, 26, 63.], and continues todevelop as new MMPs are identified. For example, collagenase-3 (MMP-13)was cloned from breast cancer cells in 1994, and the first report thatit could be involved in arthritis appeared in 1995 [Freiji, J. M.;Diez-Itza, I.; Balbin, M.; Sanchez, L. M.; Blasco, R.; Tolivia, J.;Lopez-Otin, C. J. Biol. Chem. 1994, 269, 16766; Flannery, C. R.; Sandy,J. D. 102-17, 41st Ann. Meet. Orth Res. Soc. Orlando, Fla. Feb. 13-16,1995.]. Evidence is accumulating that implicates MMP-13 in thepathogenesis of arthritis. A major structural component of articularcartilage, type II collagen, is the preferred substrate for MMP-13 andthis enzyme is significantly more efficient at cleaving type II collagenthan the other collagenases [Knauper, V.; Lopez-Otin, C.; Smith, B.;Knight, G.; Murphy, G. J. Biol. Chem., 1996, 271, 1544-1550; Mitchell,P. G.; Magna, H. A.; Reeves, L. M.; Lopresti-Morrow, L. L.; Yocum, S.A.; Rosner, P. J.; Geoghegan, K. F.; Hambor, J. E. J. Clin. Invest.1996, 97, 761.]. MMP-13 is produced by chondrocytes, and elevated levelsof MMP-13 has been found in human osteoarthritic tissues [Reboul, P.;Pelletier, J-P.; Hambor, J.; Magna, H.; Tardif, G.; Cloutier, J-M.;Martel-Pelletier, J. Arthritis Rheum. 1995, 38 (Suppl. 9), S268;Shlopov, B. V.; Mainardi, C. L.; Hasty, K. A. Arthritis Rheum. 1995, 38(Suppl. 9), S313; Reboul, P.; Pelletier, J-P.; Tardif, G.; Cloutier,J-M.; Martel-Pelletier, J. J. Clin. Invest. 1996, 97, 2011]. Potentinhibitors of MMPs were described over 10 years ago, but the poorbioavailability of these early peptidic, substrate mimetic MMPinhibitors precluded their evaluation in animal models of arthritis.More bioavailable, non-peptidic MMP inhibitors may be preferred for thetreatment of diseases mediated by MMPs.

TNF-α converting enzyme catalyzes the formation of TNF-α from membranebound TNF-α precursor protein. TNF-α is a pro-inflammatory cytokine thatis now thought to have a role in rheumatoid arthritis, septic shock,graft rejection, insulin resistance and HIV infection in addition to itswell documented antitumor properties. For example, research withanti-TNF-α antibodies and transgenic animals has demonstrated thatblocking the formation of TNF-α inhibits the progression of arthritis[Rankin, E. C.; Choy, E. H.; Kassimos, D.; Kingsley, G. H.; Sopwith, A.M.; Isenberg, D. A.; Panayi, G. S. Br. J Rheumatol. 1995, 34, 334;Pharmaprojects, 1996, Therapeutic Updates 17 (October), 197. Thisobservation has recently been extended to humans as well. Otherconditions mediated by TNF-α are congestive heart failure, cachexia,anorexia, inflammation, fever, inflammatory disease of the centralnervous system, and inflammatory bowel disease.

It is expected that small molecule inhibitors of gelatinase and TACEtherefore have the potential for treating a variety of disease states.While a variety of MMP and TACE inhibitors have been identified anddisclosed in the literature, the vast majority of these molecules arepeptidic or peptide-like compounds that may have bioavailability andpharmacokinetic problems that would limit their clinical effectiveness.Low molecular weight, potent, long-acting, orally bioavailableinhibitors of gelatinases, collagenases and/or TACE are therefore highlydesirable for the potential chronic treatment of the above mentioneddisease states. Several non-peptidc, sulfur-containing hydroxamic acidshave recently been disclosed and are listed below.

U.S. Pat. Nos. 5,455,258, 5,506,242 and 5,552,419, as well as Europeanpatent application EP606,046A1 and WIPO international publicationsWO96/00214 and WO97/22587 disclose non-peptide matrix metalloproteinaseinhibitors of which the compound CGS27023A is representative. Thediscovery of this type of MMP inhibitor is further detailed byMacPherson, et. al. in J. Med. Chem., (1997),40, 2525. Additionalpublications disclosing sulfonamide based MMP inhibitors which arevariants of the sulfonamide-hydroxamate shown below, or the analogoussulfonamide-carboxylates, are European patent application EP-757984-A1and WIPO international publications WO95/35275, WO95/35276, WO96/27583,WO97/19068 and WO97/27174.

Publications disclosing β-sulfonamide-hydroxamate MMP inhibitor analogsof CGS 27023A in which the carbon alpha to the hydroxamic acid has beenjoined in a ring to the sulfonamide nitrogen, as shown below, includeWIPO international publications WO96/33172 and WO97/20824.

The German patent application DE19,542,189-A1 discloses additionalexamples of cylic sulfonamides as MMP inhibitors. In this case thesulfonamide-containing ring is fused to a phenyl ring to form anisoquinoline.

Analogs of the sulfonamide-hydroxamate MMP inhibitors in which thesulfonamide nitrogen has been replaced by a carbon atom, as shown in thegeneral structure below, are European patent application EP-780386-A1and WIPO international publication WO97/24117.

DESCRIPTION OF THE INVENTION

This invention provides TACE and MMP inhibitors having the formula

B

wherein B is

P and Q are

provided that when

P is

Q is

and vice versa;

T, U, W, and X are each, independently, carbon or nitrogen, providedthat when T or U is carbon, either may be optionally substituted withR¹;

Y is carbon, nitrogen, oxygen or sulfur, provided that at least one ofT, U, W, X, and Y is not carbon, and further provided that no more than2 of T, U, W, and X are nitrogen;

is a phenyl ring or is a heteroaryl ring of ring 5-6 atoms which maycontain 0-2 heteratoms selected from nitrogen, oxygen, and sulfur, inaddition to any heteroatoms defined by W or X; wherein the phenyl orheteroaryl ring may be optionally mono-, di-, or tri-substituted withR¹;

Z is a phenyl, naphthyl, heteroaryl, or heteroaryl fused to phenyl,wherein the heteroaryl moiety contains of 5-6 ring atoms and 1-3heteroatoms selected from nitrogen, oxygen, or sulfur; wherein thephenyl, naphthyl, heteroaryl, or phenyl fused heteroaryl moieties may beoptionally mono-, di-, or tri-substituted with R¹;

R¹ is hydrogen, halogen, alkyl of 1-8 carbon atoms, alkenyl of 2-6carbon atoms, alkynyl of 2-6 carbon atoms, cyclocalkyl of 3-6 carbonatoms, —(CH₂)_(n)Z, —OR², —CN, —COR², perfluoroalkyl of 1-4 carbonatoms, —CONR²R³, —S(O)_(x)R² —OPO(OR²)OR³, —PO(OR²)R³, —OC(O)NR²R³,—COOR², —CONR²R³, —SO₃H, —NR²R³, —NR²COR³, —NR²COOR³, —SO₂NR²R³, —NO₂,—N(R²)SO₂R³, —NR²CONR²R³,—NR²C(═NR³)NR²R³, —SO₂NHCOR⁴, —CONHSO₂R⁴,-tetrazol-5-yl, —SO₂NHCN, —SO₂NHCONR²R³, or Z;

V is a saturated or partially unsaturated heterocycloalkyl ring of 5-7ring atoms having 1-3 heteroatoms selected from N, O, or S, which may beoptionally mono-, or di-substituted with R²;

R² and R³ are each, independently, hydrogen, alkyl of 1-8 carbon atoms,alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of3-6 carbon atoms; perfluoroalkyl of 1-4 carbon atoms, Z or V;

R⁴ is alkyl of 1-8 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of2-6 carbon atoms, cycloalkyl of 3-6 carbon atoms; perfluoroalkyl of 1-4carbon atoms, Z or V;

R⁵ is hydrogen, alkyl of 1-8 carbon atoms, alkenyl of 2-6 carbon atoms,alkynyl of 2-6 carbon atoms, Z, or V;

n=1-6;

x=0-2

or a pharmaceutically acceptable salt thereof.

The compounds of this invention are shown to inhibit the enzymes MMP-1,MMP-9, MMP-13 and TNF-α converting enzyme (FACE) and are thereforeuseful in the treatment of arthritis, tumor metastasis, tissueulceration, abnormal wound healing, periodontal disease, graftrejection, insulin resistance, bone disease and HIV infection.

Pharmaceutically acceptable salts can be formed from organic andinorganic acids, for example, acetic, propionic, lactic, citric,tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic,hydrochloric, hydrobromic, phosphoric, nitric, sulfuric,methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfonic,camphorsulfonic, and similarly known acceptable acids when a compound ofthis invention contains a basic moiety. Salts may also be formed fromorganic and inorganic bases, preferably alkali metal salts, for example,sodium, lithium, or potassium, when a compound of this inventioncontains an acidic moiety.

Alkyl, alkenyl, alkynyl, and perfluoroalkyl include both straight chainas well as branched moieties. The definitions of alkyl, alkenyl,alkynyl, and cycloalkyl include alkyl, alkenyl, alkynyl, and cycloalkylmoieties which are unsubstituted (carbons bonded to hydrogen, or othercarbons in the chain or ring) or may be mono- or poly-substituted withR¹. Halogen means bromine, chlorine, fluorine, and iodine. Preferredheteroaryl rings include pyrrole, furan, thiophene, pyridine,pyrimidine, pyridazine, pyrazine, triazole, pyrazole, imidazole,isothiazole, thiazole, isoxazole and oxazole. Preferred “heteroarylfused to phenyl” rings indole, isoindole, benzofuran, benzothiophene,quinoline, isoquinoline, quinoxaline, quinazoline, benzotriazole,indazole, benzimidazole, benzothiazole, benzisoxazole, and benzoxazole.The term “saturated or partially unsaturated heterocycloalkyl ring”means a saturated or partially unsaturated (but not aromatic, or fullysaturated) heterocycle having 5-7 ring atoms, and containing 1-3heteroatoms selected from N, O, or S. Preferred saturated or partiallyunsaturated heterocycloalkyl rings include piperidine, piperazine,morpholine, tetrahydropyran, thiomorpholine, or pyrrolidine. When amoiety contains more than substituent with the same designation (i.e.,phenyl tri-substituted with R¹) each of those substituents (R¹ in thiscase) may be the same or different.

The compounds of this invention may contain an asymmetric carbon atomand some of the compounds of this invention may contain one or moreasymmetric centers and may thus give rise to optical isomers anddiastereomers. While shown without respect to stereochemistry in B, thepresent invention includes such optical isomers and diastereomers; aswell as the racemic and resolved, enantiomerically pure R and Sstereoisomers; as well as other mixtures of the R and S stereoisomersand pharmaceutically acceptable salts thereof.

Preferred compounds of this invention are those in which:

B is

or a pharmaceutically acceptable salt thereof.

More preferred compounds of this invention are those in which:

B is

W and X are carbon; and

T is nitrogen;

U is carbon, optionally substituted with R¹

or a pharmaceutically acceptable salt thereof.

Still more preferred compounds of this invention are those in which:

B is

W and X are carbon; and

T is nitrogen;

U is carbon, optionally substituted with R¹

P is

and Q is

is phenyl or pyrazole, each optionally mono-, di-, or tri-substitutedwith R¹;

or a pharmaceutically acceptable salt thereof.

When R⁵ is Z, it is preferred that Z is phenyl or pyridyl, eachoptionally mono-, di-, or tri-substituted with R¹.

It is preferred that the Z moiety bonded to the sulfur of thesulfonamide of B, is phenyl optionally mono-substituted with R¹ and R¹is OR² or Z. When R¹ is Z it is preferred that Z is phenyl, or pyridyl,each optionally mono-, di-, or tri-substituted with R¹. When R¹ is OR²,it is preferred that R² is alkyl of 1-8 carbon atoms or Z, with Z beingphenyl or pyridyl, each optionally mono-, di-, or tri-substituted withR¹.

The compounds of this invention can be prepared according to thefollowing schemes from commercially available starting materials orstarting materials which can be prepared using to literature procedures.Typical known starting materials are shown below (I-XXI). These schemes,which follow thereafter, show the preparation of representativecompounds of this invention.

Compound I

a) Springer, R H; Scholten, M B; O'Brien, D E, Novinson, T; Miller, J P;Robins, R K J. Med. Chem. (1982), 25(3), 235-42.

b) Elworthy, T. R.; Ford, A. P. D.; et.al. J. Med. Chem. (1997), 40(17),2674-2687.

Compound II

Masui, T; TAkura, T; JP 46043792; JP 690307; CAN 76:59604

Compound III

Camparini, A; Ponticelli, F; Tedeschi, P J. Chem. Soc., Perkin Trans.1(1982), 10, 2391-4.

Compound IV

Abdalla, G M; Sowell. J W J. Heterocycl. Chem. (1990), 27 (5), 1201-7.

Compound V

a) Denzel, T; Hoehn, H J. Heterocyclic Chem. (1977), 14, 813-817.

b) Al-Shaar, A H M; Chambers, R K; Gilmour, D W; Lythgoe, D J;McClenaghan, I; Ramsden, C A J. Chem. Soc.; Perkin Trans. I (1992) 21,2789-2812.

c) Elworthy, T. R.; Ford, A. P. D.; et.al. J. Med. Chem. (1997), 40(17),2674-2687.

Compound VI

a) Forbes, I T; Johnson, C N; Jones, G E; Loudon, J; Nicholass, J M J.Med. Chem (1990) 2640-2645.

b) Kan, M A; Guarconi, A E J. Heterocyclic Chem (1977) 14, 807-812.

Compound VII

a) Forbes, I T; Johnson, C N; Jones, G E; Loudon, J; Nicholass, J M J.Med. Chem (1990) 2640-2645.

b) Kan, M A; Guarconi, A E J. Heterocyclic Chem (1977) 14, 807-812.

Compound VIII

Richardson, T O; Neale, N; Carwell, N J. Heterocyclic. Chem. (1995), 32,359-361.

Baker, J M; Huddleston, P R; Keenan, G J J. Chem Research Miniprint,(1982) 6, 1726-1746.

Compound IX

a) Forbes, I T; Johnson, C N; Jones, G E; Loudon, J; Nicholass, J M J.Med. Chem (1990) 2640-2645.

b) Kan, M A; Guarconi, A E J. Heterocyclic Chem (1977) 14, 807-812.

Compounds X, XI and XII

Elworthy, T. R.; Ford, A. P. D.; et.al. J. Med. Chem. (1997), 40(17),2674-2687.

Compound XIII

Heterocycles, (1997), 45, 980.

Compound XIV

Yokoyama, Naokata. Eur. Pat. Appl., 61 pp. CODEN: EPXXDW. EP 115469 A1840808.

Compound XV

Mendes, Etienne; Vernieres, Jean Claude; Simiand, Jacques Edouard;Keane, Peter Eugene. Eur. Pat. Appl., 12 pp. CODEN: EPXXDW. EP 346207 A1891213.

Compound XVI

Mendes, Etienne; Vernieres, Jean Claude; Simiand, Jacques Edouard;Keane, Peter F Eugene. Eur. Pat. Appl., 12 pp. CODEN: EPXXDW. EP 346207A1 891213.

Compound XVII

Morita, Yoshiharu; Wagatsuma, Kazuo. Japan. Kokai, 4 pp. CODEN: JKXXAF.JP 50058094 750520 Showa.

Compounds XVII and XIX

Armitage, Bernard John; Leslie, Bruce William; Miller, Thomas Kerr;Morley, Christopher. PCT Int. Appl., 110 pp. CODEN: PIXXD2. WO 9500511A1 950105.

Compound XX

Minami, S.; Matsumoto, J.; Kawaguchi, K.; Mishio, S.; Shimizu, M.;Takase, Y.; Nakamura, S. (Dainippon Pharmaceutical Co., Ltd., Japan)Japan. Kokai, 3 pp. CODEN: JKXXAF. JP 50014697 750215 Showa.

Compound XXI

Kihara, N.; Tan, H.; Takei, M.; Ishihara, T. (Mitsui PechochemicalIndustries, Ltd., Japan; Suntory, Ltd.) Jpn. Kokai Tokyo Koho, 11 pp.CODEN: JKXXAF. JP 62221686 A2 870929 Showa.

The compounds of this invention can be prepared using conventionaltechniques known to those skilled in the art of organic synthesis. Thefollowing scheme (Scheme I) illustrates the reaction sequence employed.In the schemes which follow, the moiety A is defined as the bicyclicheteroaryl moiety of B, as shown immediately below:

For purposes of illustration only, wherein the bicyclic heteroaryl groupA shown is a quinoline, 4-chloro-7-trifluoromethylquinoline-3-carboxylicacid ethyl ester, prepared from the corresponding aniline, is reactedwith N-benzyl-p-methoxybenzenesulfonamide, wherein Z isp-methoxybenzene, to provide the requisite N,N-disubstitutedsulfonamido-ester which is then converted into the correspondinghydroxamic acid in two steps.

Alternatively, the 4-chloroquinoline carboxylic acid ester could befirst reacted with R⁷—NH₂ and the resulting 4-(R⁷-amino)quinolinecarboxylic acid ester then reacted with the appropriate Z—SO₂—Cl.Hydrolysis of the ester and reaction with hydroxylamine hydro-chloridewould then give the invention compound.

Functionalization of the quinoline ring via a palladium catalyzed Heckcoupling between the iodoquinoline and tributylvinyltin is shown inScheme II. α,β-Unsaturated esters and amides can be coupled to thehaloquinoline via Heck reactions. A variety of other trialkyltinreagents are readily available and may be similarly used. Boronic acids,commercially available or readily prepared, may also be coupled to theiodoquinoline using the Suzuki reaction.

Functionalization of haloquinolines may also be accomplished viapalladium catalyzed couplings of alkynes, as illustrated in Scheme III.Hydrogenation of the alkynes accesses the olefins and alkanes as well.

Schemes IV and V illustrate two methods for incorporating amino groupsinto the substituent attached to the sulfonamide nitrogen of thecompounds of the invention. Thus, in Scheme IV the NH-sulfonamide isalkylated with propargyl bromide to provide the propargyl sulfonamide.This alkyne is reacted with paraformaldehyde in the presence of aprimary or secondary amine and cuprous chloride to give the propargylamine which is converted, as before, to the desired hydroxamic acid.

In Scheme V, selective hydrolysis of the ester of thep-carboethoxybenzyl sulfonamide group provides a mono-carboxylic acid.This acid may be converted into an amide (not shown), followed byconversion of the second ester, A—CO₂R, into the correspondinghydroxamate, or reduced to the corresponding alcohol with diborane. Thealcohol may be converted into the analogous amine via the benzylicbromide, followed by conversion of the the ester, A—CO₂R, into thecorresponding hydroxamate.

Methods for synthesizing variations of substituents on the sulfonyl arylgroup are shown in Schemes VI through VIII. As shown in Scheme VI,biaryl sulfonyl groups are synthesized by Suzuki couplings on abromo-substituted benzene sulfonamide. The starting bromo-substitutedbenzene sulfonamide is synthesized from the commercially availablebromobenzenesulfonyl chloride and the amino-acid or amino-ester,H₂N—A—CO₂R, followed by alkylation of the resulting NH-sulfonamide.Alternatively, the bromo aryl sulfonamide is converted into thecorresponding boronic acid by the method of Ishiyama, et.al. [J. Org.Chem. (1995), 60, 7508] followed by coupling with an appropriate arylhalide.

Methods for synthesizing sulfonyl aryl ethers are shown in Schemes VIIthrough IX. In Scheme VII biaryl ethers, or aryl heteroaryl ethers, aresynthesized starting from the known sulfonyl chlorides (see for example:Zook S E; Dagnino, R; Deason, M E, Bender, S L; Melnick, M J WO97/20824).

Alternatively, the biaryl ethers may be prepared from the correspondingboronic acids or via the sulfonyl phenols as shown in Scheme VIII.

Aryl ethers may also be prepared via displacement of the fluorine from apara-fluorobenzene sulfonamide, as shown in Scheme IX. Aryl or alkylethers may be prepared in this manner.

Scheme X illustrates the synthesis of pyrazolopyridines,isoxazolopyridines, and isothiazolopyridines of the invention. Thus, anaminopyrazole, aminoisoxazole or aminoisothiazole is condensed withethoxymethylene malonate to provide the intermediate, B. This compoundis converted into the pyrazolopyridine, isoxazolopyridine, orisothiazolopyridine, C, by heating at 240° C. Compound C is thenconverted into the chloro-ester, D, via reaction with phosphorusoxychloride. Displacement of the chloro substituent with a sulfonamidethen gives compound E. Hydrolysis of the ester and conversion of thecarboxylate into the hydroxamate then gives compound G. Salts of theinvention compounds can be prepared according to standard procedures.

Pyrazolo[1,5-b]pyrimidines of the invention are prepared according toscheme XI using reactions as described for scheme X.

The following specific examples illustrate the preparation ofrepresentative compounds of this invention. The starting materials,intermediates, and reagents are either commercially available or can bereadily prepared following standard literature procedures by one skilledin the art of organic synthesis.

EXAMPLE 14-[Benzyl-(4-methoxy-benzenesulfonyl)-amino]-7-trifluoromethylquinoline-3-carboxylicAcid Ethyl Ester

To a solution of 1.85 g (6.67 mmol) of N-benzyl4-methoxyphenylsulphonamide in 15 mL of DMF was added, in one portion,0.267 g (6.67 mmol) of 60% sodium hydride and the resulting mixture wasstirred at room temperature under nitrogen for 15 min. Ethyl4-chloro-7-trifluoromethyl-3-quinolinecarboxylate (2.02 g, 6.67 mmol)was then added to the solution in one portion and the resulting mixturewas heated at 85° C. for 24 h. The reaction mixture was then cooled toroom temperature, poured into a mixture of water (300 mL) and HCl (1N,aqueous, 100 mL) and extracted with ethyl acetate (2×100 mL). Thecombined organic layers were dried over magnesium sulfate, filtered andconcentrated in vacuo. The residue was then chromatographed on silicagel eluting with 15%-50% ethyl acetate/hexane to give 3.11 g (88%) ofthe desired product. Electrospray Mass Spec 545.1 (M+H).

EXAMPLE 24-[Benzyl-(4-methoxy-benzenesulfonyl)-amino]-8-trifluoromethylquinoline-3-carboxylicAcid Ethyl Ester

In the same manner as described in Example 1, 1.012 g (3.34 mmol) ofethyl 4-chloro-8-trifluoromethyl-3-quinolinecarboxylate provided 1.509 g(83%) of the desired quinoline ester as a white solid. Electrospray MassSpec 545.1 (M+H).

EXAMPLE 34-[Benzyl-(4-methoxy-benzenesulfonyl)-amino]-6-bromo-quinoline-3-carboxylicAcid Ethyl Ester

In the same manner as described in Example 1, 0.848 g (2.70 mmol) ofethyl 6-bromo-4-chloro-3-quinolinecarboxylate provided 1.418 g (95%) ofthe desired quinoline ester as a white solid. Electrospray Mass Spec557.1 (M+H).

EXAMPLE 44-[Benzyl-(4-methoxy-benzenesulfonyl)-amino]-7-bromo-quinoline-3-carboxylicAcid Ethyl Ester

In the same manner as described in Example 1, 0.777 g (2.47 mmol) ofethyl 7-bromo-4-chloro-3-quinolinecarboxylate provided 1.169 g (85%) ofthe desired quinoline ester as a white solid. Electrospray Mass Spec557.1 (M+H).

EXAMPLE 54-[Benzyl-(4-methoxy-benzenesulfonyl)-amino]-6-trifluoromethylquinoline-3-carboxylicAcid Ethyl Ester

In the same manner as described in Example 1, 1.216 g (4.02 mmol) ofethyl 4-chloro-6-trifluoromethyl-3-quinolinecarboxylate provided 2.171 g(99%) of the desired quinoline ester as a white solid. Electrospray MassSpec 545.0 (M+H).

EXAMPLE 64-[Benzyl-(4-methoxy-benzenesulfonyl)-amino]-7-trifluoromethylquinoline-3-carboxylicAcid

To a solution of 1.065 g (2.00 mmol) of the product from Example 1 in 4mL of methanol/THF (1:1) was added 2 mL of 1N sodium hydroxide solutionand the resulting mixture was stirred at 25° C. for 18 h. The reactionwas then acidified with 1N HCl and extracted with ethyl acetate (200mL). The organic layer was washed with water and brine, dried overMgSO₄, filtered and concentrated in vacuo. The resulting residue wastriturated with ethyl acetate/hexane (1:9) and filtered to provide 828mg (82%) of the desired carboxylic acid as a white solid. ElectrosprayMass Spec 517.1 (M+H)

EXAMPLE 74-[Benzyl-(4-methoxy-benzenesulfonyl)-amino]-8-trifluoromethylquinoline-3-carboxylicAcid

In the same manner as described in Example 6, 1.255 g (2.64 mmol) of theproduct from Example 2 provided 0.988 g (83%) of the desired quinolineacid as a white solid. Electrospray Mass Spec 517.1 (M+H).

EXAMPLE 84-[Benzyl-(4-methoxy-benzenesulfonyl)-amino]-6-bromo-quinoline-3-carboxylicAcid

In the same manner as described in Example 6, 1.198 g (2.16 mmol) of theproduct from Example 3 provided 0.921 g (81%) of the desired quinolineacid as a white solid. Electrospray Mass Spec 529.0 (M+H).

EXAMPLE 94-[Benzyl-(4-methoxy-benzenesulfonyl)-amino]-7-bromo-quinoline-3-carboxylicAcid

In the same manner as described in Example 6, 0.969 g (1.74 mmol) of theproduct from Example 4 provided 0.804 g (87%) of the desired quinolineacid as a white solid. Electrospray Mass Spec 529.0 (M+H).

EXAMPLE 104-(Benzyl-(4-methoxy-benzenesulfonyl)-amino]-6-trifluoromethylquinoline-3-carboxylicAcid

In the same manner as described in Example 6, 2.043 g (3.75 mmol) of theproduct from Example 5 provided 1.82 g (88%) of the desired quinolineacid as a white solid. Electrospray Mass Spec 515.0 (M−H).

EXAMPLE 114-[Benzyl-(4-methoxy-benzenesulfonyl)-amino]-7-trifluoromethylquinoline-3-carboxylicAcid Hydroxyamide

To a solution of 0.636 g (1.26 mmol) of the product from Example 6 in12.5 mL of dichloromethane was added 0.05 mL of DMF followed by 1.26 mL(2.52 mmol) of 2 M oxalyl chloride and the resulting reaction mixturewas stirred at room temperature for 1 h.

In a separate flask, 2.6 mL (19 mmol) of triethylamine was added to a 0°C. mixture of 350 mg (13 mmol) of hydroxylamine hydrochloride in 14 mLof THF and 3.5 mL of water. After this mixture had been stirred for 15min at 0° C., the acid chloride solution was added to it in one portionand the resulting solution was allowed to warm to room temperature andstirred for another 4 h. Water was then added to the reaction flask and0.488 g (75%) product was collected via filtration. Electrospray MassSpec 532.1 (M+H)

EXAMPLE 124-[Benzyl-(4-methoxy-benzenesulfonyl)-amino]-8-trifluoromethylquinoline-3-carboxylicAcid Hydroxyamide

In the same manner as described in Example 11, 0.444 g (3.75 mmol) ofthe product from Example 7 provided 0.143 g (31%) of the desiredquinoline hydroxamic acid as a cream colored solid. Electrospray MassSpec 532.1 (M+H).

EXAMPLE 134-[Benzyl-(4-methoxy-benzenesulfonyl)-amino]-6-bromo-quinoline-3carboxylicAcid Hydroxyamide

In the same manner as described in Example 11, 0.527 g (1.00 mmol) ofthe product from Example 8 provided 0.367 g (68%) of the desiredquinoline hydroxamic acid as a off-white solid. Electrospray Mass Spec541.9 (M+H).

EXAMPLE 144-[Benzyl-(4-methoxy-benzenesulfonyl)-amino]-7-bromo-quinoline-3-carboxylicAcid Hydroxyamide

In the same manner as described in Example 11, 0.527 g (1.00 mmol) ofthe product from Example 9 provided 0.280 g (52%) of the desiredquinoline hydroxamic acid as a white solid. Electrospray Mass Spec 541.9(M+H).

EXAMPLE 154-[Benzyl-(4-methoxy-benzenesulfonyl)-amino]-6-trifluoromethylquinoline-3-carboxylicAcid Hydroxyamide

In the same manner as described in Example 11, 0.527 g (1.06 mmol) ofthe product from Example 10 provided 0.435 g (77%) of the desiredquinoline hydroxamic acid as a cream colored solid. Electrospray MassSpec 532.1 (M+H).

EXAMPLE 164-[(4-Methoxybenzenesulfonyl)-pyridin-3-ylmethylamino]-7-trifluoromethyl-quinoline-3-carboxylicAcid Hydroxyamide

Following the procedure of example 1 and substitutingN-(3-pyridinylmethyl)-4-methoxybenzenesulfonamide forN-benzyl-4-methoxybenzenesulfonamide, the intermediate4-[(4-methoxybenzenesulfonyl)-pyridin-3-ylmethylamino]-7-trifluoromethyl-quinoline-3-carboxylicacid ethyl ester is obtained. Following the procedures of example 6 and11, the title product is obtained. Electrospray Mass Spec 533.0 (M+H).

EXAMPLE 174-[Benzyl-(4-methoxybenzenesulfonyl)-amino]-8-t-butyl-quinoline-3-carboxylicAcid Hydroxyamide

In the same manner as described in Example 1, 1.167 g (4.00 mmol) ofethyl 4-chloro-8-butyl-3-quinolinecarboxylate provided 1.413 g (66%) ofthe desired quinoline ester as a white solid. Electrospray Mass Spec533.3 (M+H).

In the same manner as described in Example 6, 1.065 g (2.00 mmol) of theester provided 0.478 g (47%) of the desired quinoline acid as a whitesolid. Electrospray Mass Spec 503.3 (M−H).

Following the procedures of example, the title compound is obtained fromthe carboxylic acid. Electrospray Mass Spec. 520.3 (M+H).

EXAMPLE 184-[Benzyl-(4-methoxybenzenesulfonyl)-amino]-8-methyl-quinoline-3-carboxylicAcid Hydroxyamide

In the same manner as described in Example 1, 1.00 g (4.00 mmol) ofethyl 4-chloro-8-methyl-3-quinolinecarboxylate provided 0.531 g (27%) ofthe desired quinoline ester as a white solid. Electrospray Mass Spec491.3 (M+H).

In the same manner as described in Example 6, 0.470 g (0.851 mmol) ofthe ester provided 0.160 g (41%) of the desired quinoline acid as awhite solid. Electrospray Mass Spec 461.3 (M−H).

Following the procedure of example 11, the title compound is obtainedfrom the carboxylic acid. Electrospray Mass Spec. 478.3 (M+H).

EXAMPLE 194-[Benzyl-(4-methoxybenzenesulfonyl)-amino]-8-ethyl-quinoline-3-carboxylicAcid Hydroxyamide

In the same manner as described in Example 1, 1.055 g (4.00 mmol) ofethyl 4-chloro-8-ethyl-3-quinolinecarboxylate provided 0.670 g (33%) ofthe desired quinoline ester as a white solid. Electrospray Mass Spec505.3 (M+H).

In the same manner as described in Example 6, 0.615 g (1.22 mmol) of theproduct from Example 7 provided 0.353 g (60%) of the desired quinolineacid as a white solid. Electrospray Mass Spec 475.3 (M−H).

Following the procedure of example 11, the title compound is obtainedfrom the carboxylic acid. Electrospray Mass Spec. 492.3 (M+H).

EXAMPLE 204-[Benzyl-(4-methoxybenzenesulfonyl)-amino]-8-(1-methylethyl)-quinoline-3-carboxylicAcid Hydroxyamide

In the same manner as described in Example 1, 1.11 g (4.00 mmol) ofethyl 4-chloro-8-isopropyl-3-quinonecarboxylate provided 0.754 g (36%)of the desired quinoline ester as a white solid. Electrospray Mass Spec519.3 (M+H).

In the same manner as described in Example 6, 0.686 g (0.127 mmol) ofthe ester provided 0.532 g (82%) of the desired quinoline acid as awhite solid. Electrospray Mass Spec 489.2 (M−H).

In the same manner as described in Example 11, 0.440 g (0.897 mmol) ofthe hydroxamic acid provided 0.270 g (60%) of the desired quinolinehydroxamic acid. Electrospray Mass Spec. 506.3 (M+H).

EXAMPLE 214-[(Ethyl-(4-methoxy-benzenesulfonyl)-amino]-8-iodo-quinoline-3-carboxylicAcid Ethyl Ester

In the same manner as described in Example 1 and substitutingN-ethyl-4-methoxybenzenesulfonamide forN-benzyl-4-methoxybenzenesulfonamide, 1.076 g (5.00 mmol) of ethyl8-iodo-4-chloro-3-quinolinecarboxylate provided 2.438 g (4.51 mmol, 90%)of the desired quinoline ester as a white solid. Electrospray Mass Spec541.0 (M+H).

EXAMPLE 224-[Ethyl-(4-methoxy-benzenesulfonyl)-amino]-8-vinyl-quinoline-3-carboxylicAcid Ethyl Ester

The product from example 21 (2.438 g, 4.51 mmol) in 150 mL DMF was addedtributylvinyltin (1.43 g, 4.51 mmol),tetrakis(triphenylphospine)palladium(0) (520 mg, 10%), cuprious iodide(171 mg, 20%), and 5 mL triethylamine. The mixture was stirred under N2and heated at 85° C. for 18 hours. The it was poured into a mixture(1:1) of 400 mL saturated sodium bicarbonate and saturated amoniumchloride and extracted with ethyl acetate (2×200 mL). The combinedorganic layers were dried over magnesium sulfate, filtered andconcentrated on a rotary evaporator. The residue was columnchromatographed using 300 mL silica gel and gradient elution withhexane/ethyl acetate (100˜0%). This provided 1.706 g (3.88 mmol, 86%) ofthe desired quinoline ester. Electrospray Mass Spec 441.1 (M+H).

EXAMPLE 234-[Methyl-(4-methoxy-benzenesulfonyl)-amino]-6-phenylethynyl-quinoline-3-carboxylicAcid Ethyl Ester

Combining the procedures of examples 1 and 22, and substitutingphenylacetylene for vinyltin, N-ethyl-4-methoxybenzenesulfonamide forN-benzyl-4-methoxybenzenesulfonamide, the intermediate4-[ethyl-(4-methoxy-benzenesulfonyl)-amino]-6-phenylethynyl-quinoline-3-carboxylicacid ethyl ester is obtained from ethyl-4-chloro-3-quinolinecarboxylate.Electrospray Mass Spec 515.3 (M+H).

EXAMPLE 244-[Ethyl-(4-methoxy-benzenesulfonyl)-amino]-8-vinyl-quinoline-3-carboxylicAcid

In the same manner as described in Example 6, 1.593 g (3.62 mmol) of theproduct from Example 22 provided 1.333 g (89%) of the desired quinolineacid as a white solid. Electrospray Mass Spec 411.1 (M−H).

EXAMPLE 254-[Methyl-(4-methoxy-benzenesulfonyl)-amino]-6-phenylethynyl-quinoline-3-carboxylicAcid

In the same manner as described in Example 6, the title compound wassynthesized from the product of example 23. Electrospray Mass Spec 485.3(M−H).

EXAMPLE 264-[Benzyl-(4-methoxy-benzenesulfonyl)-amino]-6-nitro-quinoline-3-carboxylicAcid

In the same manner as described in Example 1 and 6, 5.613 g (20.0 mmol)ethyl 4-chloro-6-nitro-3-quinolinecarboxylate provided 2.676 g (27% fortwo steps) of the title compound as a white solid. Electrospray MassSpec 492.3 (M−H).

EXAMPLE 274-[Methyl-(4-methoxy-benzenesulfonyl)-amino]-8-bromo-quinoline-3-carboxylicAcid

Combining the procedures of example 1 and 6, and substitutingN-methyl-4-methoxybenzenesulfonamide forN-benzyl-4-methoxybenzenesulfonamide, the intermediate8-bromo-4-[methyl-(4-methoxy-benzenesulfonyl)-amino]-quinoline-3-carboxylicacid is obtained. Electrospray Mass Spec 449.2 (M−H).

EXAMPLE 284-{Methyl-(4-(pyridin-4-yloxy)-benzenesulfonyl]-amino}-6-iodo-quinoline-3-carboxylicAcid

Combining the procedures of example 1 and 6, and substitutingN-methyl-4-(pyridin-4-yloxy)-benzenesulfonamide the intermediate6-iodo-4-{methyl-(4-(pyridin-4-yloxy)-benzenesulfonyl]-amino}-quinoline-3-carboxylicacid is obtained from ethyl 6-iodo-4-chloro-3-quinolinecarboxylate.Electrospray Mass Spec 559.9 (M−H).

EXAMPLE 294-[Ethyl-(4-methoxy-benzenesulfonyl)-amino]-8-vinyl-quinoline-3-carboxylicAcid Hydroxyamide

In the same manner as described in Example 11, 0.484 g (1.17 mmol) ofthe product from Example 24 provided 0.360 g (72%) of the desiredquinoline hydroxamic acid. Electrospray Mass Spec. 428.0 (M+H).

EXAMPLE 304-[Benzyl-(4-methoxy-benzenesulfonyl)-amino]-6-nitro-quinoline-3-carboxylicAcid Hydroxyamide

In the same manner as described in Example 11, 0.825 g (1.67 mmol) ofthe product from Example 26 provided 0.227 g (0.446 mmol, 26%) of thedesired quinoline hydroxamic acid. Electrospray Mass Spec. 509.0 (M+H).

EXAMPLE 314-[Methyl-(4-methoxy-benzenesulfonyl)-amino]-8-bromo-quinoline-3-carboxylicAcid Hydroxyamide

In the same manner as described in Example 11, 0.664 g (1.47 mmol) ofthe product from Example 27 provided 0.145 g (0.311 mmol, 21%) of thedesired quinoline hydroxamic acid. Electrospray Mass Spec. 468.0 (M+H).

EXAMPLE 324-{Methyl-[4-(pyridin-4-yloxy)-benzenesulfonyl]-amino}-6-iodo-quinoline-3-carboxylicAcid Hydroxyamide

To a 0° C. solution of of 4.5 mL oxalyl chloride (0.90 mmol, 2M indichloromethane) was added dropwise 0.69 mL of DMF. The resulting solidwas kept at 0° C. for another 15 minutes and followed by addition of2.50 g (4.46 mmol) of the product from Example 28 in 50 mL DMF. Themixture was stirred for 1 hour at room temperature and then kept at 0°C. for an additional 15 minutes. An aqueous solution of hydroxylamine (5mL, 50%) was then added all at once to the above solution and themixture was stirred at room temperature for 3 hours. The mixture wasnext poured into 300 mL water and extracted with dichloromethane (4×100mL). The combined organic layers were washed with brine (300 mL) anddried over magnesium sulfate. After filtration and concentration on arotary evaporator the residue was column chromatographed using gradientmethanol in ethyl acetate (20-100%) and it provided 1.36 g (2.36 mmol,53%) of the desired quinoline hydroxamic acid. Electrospray Mass Spec.576.9 (M+H).

EXAMPLE 334-{Methyl-(4-(pyridin-4-yloxy)-benzenesulfonyl]-amino}-6-iodo-quinoline-3-carboxylicAcid Hydroxyamide Hydrochloride

The product from example 32 (0.952 g, 1.65 mmol) was dissolved in 100 mLmethanol in a Parr reactor. Degussa catalyst (10% Pd-C, 200 mg) was nextadded under N2. The mixture was then hydrogenated (35 psi) for one hourat room temperature. The mixture was then filtered through a pad ofcelite and concentrated on a rotary evaporator. The residue waschromatographed with methanol and ethyl acetate (5-35%). The productobtained was next dissolved in methanol and anhydrous hydrochloride wasbubbled into the solution for 5 minutes. Removal of the solvent throughrotary evaporation and vacuum pump gave 0.707 g (1.45 mmol, 88%)product. Electrospray Mass Spec. 450.9 (M+H).

EXAMPLE 344-[Ethyl-(4-methoxy-benzenesulfonyl)-amino]-6-phenylethynyl-quinoline-3-carboxylicAcid Hydroxyamide

In the same manner as described in Example 11, 2.432 g (5.00 mmol) ofthe product from Example 25 provided 2.159 g (86%) of the desiredquinoline hydroxamic acid. Electrospray Mass Spec. 502.1 (M+H).

EXAMPLE 354-[Methyl-(4-methoxy-benzenesulfonyl)-amino]-6-phenylethyl-quinoline-3-carboxylicAcid Hydroxyamide

The product from example 34 (0.82 g, 1.64 mmol) was dissolved in 50 mLmethanol in a Parr reactor. Degussa Catalyst (10% Pd-C, 200 mg) was nextadded under N2. The mixture was hydrogenated (45 psi) for one hour atroom temperature. The mixture was then filtered through a pad of celiteand concentrated on a rotary evaporator. This gave 0.76 g (1.50 mmol,92%) product. Electrospray Mass Spec. 506.0 (M+H).

EXAMPLE 364-[(4-Methoxy-benzenesulfonyl)-pyridin-3-ylmethyl-amino]-8-methoxy-quinoline-3-carboxylicAcid Hydroxyamide

Following the procedure of Example 16 and starting with ethyl4-chloro-8-methoxy-3-quinolinecarboxylate the title compound wasobtained as a yellow powder. Electrospray Mass Spec. 495.3 (M+H).

EXAMPLE 374-[(4-Methoxy-benzenesulfonyl)-pyridin-3-ylmethyl-amino]-8-bromo-quinoline-3-carboxylicAcid Hydroxyamide

Following the procedure of Example 16 and starting with ethyl4-chloro-8-bromo-3-quinolinecarboxylate the title compound was obtainedas a white powder. Electrospray Mass Spec. 543.2 (M+H).

EXAMPLE 38 4-[(4-methoxy-benzenesulfonyl)-pyridin-3-ylmethylamino]-8-Benzyl-quinoline-3-carboxylic Acid Hydroxyamide

Following the procedure of Example 16 and starting with ethyl4-chloro-8-benzyl-3-quinolinecarboxylate the title compound was obtainedas a beige powder. Electrospray Mass Spec. 555.4 (M+H).

EXAMPLE 394-[(4-Methoxy-benzenesulfonyl)-pyridin-3-ylmethyl-amino]-8-iodo-quinoline-3-carboxylicAcid Hydroxyamide

Following the procedure of Example 16 and starting with ethyl4-chloro-8-iodo-3-quinolinecarboxylate the title compound was obtainedas a yellow powder. Electrospray Mass Spec. 590.8 (M+H).

EXAMPLE 404-[(4-Methoxy-benzenesulfonyl)-pyridin-3-ylmethyl-amino]-8-phenyl-quinoline-3-carboxylicAcid Hydroxyamide

Following the procedure of Example 16 and starting with ethyl4-chloro-8-phenyl-3-quinolinecarboxylate the title compound was obtainedas a beige powder. Electrospray Mass Spec. 541.4 (M+H).

EXAMPLE 414-[(4-Methoxy-benzenesulfonyl)-pyridin-3-ylmethyl-amino]-8-thiophen-2-yl-quinoline-3-carboxylicAcid Hydroxyamide

Combining the procedures of Examples 22, 6 and 11 and starting with4-[(4-methoxy-benzenesulfonyl)-pyridin-3-ylmethyl-amino]-8-bromo-quinoline-3-carboxylicacid ethyl ester and 2-tributylstannylthiophene the title compound wasobtained as a yellow powder. Electrospray Mass Spec. 545.0 (M+H).

EXAMPLE 42 4-[(Biphenyl-4-sulfonyl)-pyridin-3-ylmethyl-amino]-7-trifluoromethyl-quinoline-3-carboxylic Acid Hydroxyamide

Following the procedure of Example 1 and substitutingN-(3-pyridinylmethyl)-4-bromobenzenesulfonamide forN-benzyl-4-methoxybenzenesulfonamide, the intermediate4-[(4-bromobenzenesulfonyl)-pyridin-3-ylmethylamino]-7-trifluoromethyl-quinoline-3-carboxylicacid ethyl ester is obtained.

To 8.5 mL of degassed ethylene glycol dimethyl ether, was added 500 mg(0.85 mmol) of the ester, 110 mg (0.93 mmol) of phenylboronic acid, 80mg (0.07 mmol) of tetrakis(triphenylphosphine)palladium and 1.1 ml (2.2mmol) of 2M aqueous Na₂CO₃ and the mixture ws heated to reflux undernitrogen for 36 hr. The reaction was cooled to room temperature, dilutedwith ethyl acetate, washed with water and brine, dried over MgSO₄,filtered and concentrated in vacuo to give4-[(biphenyl-4-sulfonyl)-pyridin-3-ylmethyl-amino]-7-trifluoromethyl-quinoline-3-carboxylicacid ethyl ester.

This ester was converted to the title compound (off-white powder) asdescribed in Examples 6 and 11. Electrospray Mass Spec. 579.1 (M+H).

EXAMPLE 434-[(Octane-1-sulfonyl)-pyridin-3-ylmethyl-amino]-7-trifluoromethyl-quinoline-3-carboxylicAcid Hydroxyamide

Combining the procedures of Examples 1, 6 and 11 and substitutingN-(3-pyridinylmethyl)-octanesulfonamide forN-benzyl-4-methoxybenzenesulfonamide the title compound was obtained asa yellow solid. Electrospray Mass Spec. 539.5 (M+H).

EXAMPLE 444-[Pyridin-3-ylmethyl-(toluene-4-sulfonyl)-amino]-7-trifluoromethyl-quinoline-3-carboxylicAcid Hydroxyamide

Combining the procedures of Examples 1, 6 and 11 and substitutingN-(3-pyridinylmethyl)-toluenesulfonamide forN-benzyl-4-methoxybenzenesulfonamide the title compound was obtained asa white powder. Electrospray Mass Spec. 517.1 (M+H).

EXAMPLE 45 Diethyl{[(1-phenyl-5-pyrazolyl)amino]methylene}malonate

A mixture of 15.9 g. (0.10 mole) of 1-phenyl-5-aminopyrazole and 21.6 g.(0.10 mole) of diethyl ethoxymethylenemalonate was heated at 115-120° inan oil bath for 2 hours. After cooling, the crystalline mass wasrecrystallized from hot hexane containing 1% of ethanol. Cooling to roomtemperature and filtering gave 24.8 g. (75%) of off-white crystals, m.p.96-97° C.

EXAMPLE 46 Ethyl4-hydroxy-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

A mixture of 18.1 g. (0.055 mole) of diethyl{[(1-phenyl-5-pyrazolyl)amino]methylene}malonate and 150 ml of diethylphthalate was heated at 240-250° for 1 hour. The mixture was chilled anddiluted with hexane. Chilling and filtering gave crystals which werewashed with hexane and with hexane-ethanol (1:1) to give 11 g. (70%) ofoff white crystals m.p. 149-150° C. From a similar small scale run 1.75g. was recrystallized from 110 ml. of ethanol to give 1.58 g. of offwhite crystals, m.p. 149-150° C.

EXAMPLE 47 Ethyl4-chloro-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

A mixture of 5.76 g (20.33 mmol) of ethyl4-hydroxy-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate and 15.58 gof phosphorus oxychloride was refluxed 1.5 hr, chilled and poured slowlyonto crushed ice. The mixture was filtered and the solid washed withice-water and dried to give 6.0 g of solid, m.p. 89-91° C.

EXAMPLE 48 Ethyl4-chloro-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

Following the procedures of Examples 45, 46 and 47, starting from1,3-dimethyl-5-aminopyrazole, the chloro-ester is prepared. m.p. 89-90°C.

EXAMPLE 49 Ethyl4-[benzyl-(4-methoxybenzenesulfonyl)amino]-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

To a solution of 1.16 g (4.2 mmol) ofbenzyl-(4-methoxybenzenesulfonyl)amine in 6 ml of anhydrous1-methyl-2-pyrrolidinone was added 0.168 g (4.2 mmol) of sodium hydride(60% in oil) and the mixture stirred at room temperature until gasevolution ceased. The preceding mixture was added to mixture of 1.01 g(4 mmol) of ethyl4-chloro-1,3-dimethylpyrazolo[3,4-b]pyridine-5-carboxylate in 2 ml of1-methyl-2-pyrrolidinone.

The mixture was heated in an oil bath at 50° C. overnight and then washeated in an oil bath at 100° C. for 1.5 days. The mixture was pouredinto 800 ml of water and extracted with ethyl acetate. The extract waswashed with water, 2N citric acid, water, brine and dried (Na₂SO₄). Thesolvent was removed and the residue chromatographed on silica gel withhexane-ethyl acetate (2:1) as eluent to give 0.64 g of product as asolid, mp 170-172°. From a larger scale run of 5.07 g (0.02 mmol) ofethyl 4-chloro-1,3-dimethylpyrazolo[3,4-b]pyridine-5-carboxylate and 8.0g (0.0289 mmol) of benzyl-(4-methoxybenzenesulfonyl) amine (as sodiumanion) in 30 ml of 1-methyl-2-pyrrolidinone heated at 90° C. for 3 daysthere was obtained 3.65 g of product.

EXAMPLE 504-[Benzyl-(4-methoxybenzenesulfonyl)amino]-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylicAcid

A mixture of 0.48 g (0.97 mmol) of ethyl4-[benzyl-(4-methoxybenzenesulfonyl)amino]-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylateand 0.29 ml of 10N NaOH in 4 ml of tetrahydrofuran-methanol (1:1) washeated in an oil bath at 70° C. for 2 hours and the solvent removedunder vacuum. The residue was dissolved in 20 ml of H₂O and the solutionextracted with 10 ml of diethyl ether. To the aqueous layer was added 2Ncitric acid (pH 4-5) and the precipitated solid filtered and washed withH₂O to give a white solid which was dried under vacuum overnight to givecrystals, mp 165-167° C.

EXAMPLE 514-[Benzyl-(4-methoxybenzenesulfonyl)amino]-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylicAcid, Potassium Salt

A mixture of 3.60 g (7.28 mmol) of ethyl4-[benzyl-(4-methoxybenzenesulfonyl)amino]-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylateand 0.44 g (7.84 mmol) of potassium hydroxide (pellet) in 15 ml ofmethanol-water (1:1) was refluxed overnight. An additional 40 mg ofpotassium hydroxide was added and the mixture refluxed for 4 hours (allthe solid dissolved). The solvent was removed under vacuum and tolueneadded and removed under vacuum. The residue was triturated with ethylacetate, filtered and the solid washed with ethyl acetate to give 3.8 gof product as a white solid.

EXAMPLE 524-[Benzyl-(4-methoxybenzenesulfonyl)amino]-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylicAcid, Hydroxyamide

To a chilled solution of 1 ml (2 mmol) of oxalyl chloride in 8 ml of CH₂Cl₂ was added dropwise 0.154 ml (2 mmol) of N,N-dimethylformamide andthe solution stirred 15 min. To the preceding chilled solution was added0.504 g (1 mmol) of4-[benzyl-(4-methoxybenzenesulfonyl)amino]-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid, potassium salt and the mixture stirred under nitrogen for 2 hrs atroom temperature (solution A). A solution of 0.278 g (4 mmol) ofhydroxylamine hydrochloride and 0.834 ml (6 mmol) of triethylamine in 5ml of H₂O-tetrahydrofuran (1:4) was chilled at in an ice bath for 20min. and to this solution was added dropwise the chilled solution of A.The mixture was allowed to warm to room temperature and was stirredovernight. The solvent was removed and the residue extracted withCH₂Cl₂. The CH₂Cl₂ extract was washed with 2N citric acid, H₂O, 1NNaHCO₃, H₂O, brine and dried (Na₂SO₄). The solvent was removed to give0.53 g of solid. Trituration with ethyl acetate gave 0.278 g of whitesolid, mp 184-186° C.

EXAMPLE 53 Ethyl4-[(4-methoxybenzenesulfonyl)pyridin-3-ylmethylamino]-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

To a solution of 1.39 g (5 mmol) of(4-methoxybenzenesulfonyl)(3-pyridinylmethyl) amine in 4 ml of anhydrous1-methyl-2-pyrrolidinone was added 0.2 g (5 mmol) of sodium hydride (60%in oil) and the mixture stirred at room temperature until gas evolutionceased. To this mixture was added 1.15 g (4.54 mmol) of ethyl4-chloro-1,3-dimethylpyrazolo[3,4-b]pyridine-5-carboxylate and 2 ml ofanhydrous 1-methyl-2-pyrrolidinone. The mixture was stirred in a sealedtube under nitrogen in an oil bath at 90° C. for 3 days. The mixture wascooled, poured into water and extracted with ethyl acetate. The extractwas washed with H₂O, brine and dried (Na₂SO₄). The solution was filteredthrough a thin pad of hydrous magnesuim silicate and the filter padwashed with ethyl acetate. The filtrate was concentrated to drynessunder vacuum to give 1.3 g of solid. Chromatography on silica gel withethyl acetate as solvent gave 0.35 g of product as a solid, mp 152-154°C.

EXAMPLE 544-[(4-Methoxybenzenesulfonyl)pyridin-3-ylmethylamino]-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylicAcid

A mixture of 1.34 g (2.7 mmol) of ethyl4-[(4-methoxybenzenesulfonyl)pyridin-3-_ylmethylamino]-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-5-carboxylate,2.97 ml of 1N potassium hydroxide in 7.8 ml of ethanol and 4.83 ml ofwater was refluxed for 20 hr. Another 0.54 ml of 1N potassium hydroxidewas added and the mixture refluxed 4 hrs. The solvent was removed undervacuum and toluene added and removed under vacuum. The residue wasdissolved in water (20 ml) and extracted with ethyl acetate. The aqueouslayer was acidified with 2 N citric acid and the precipitated solidfiltered off and washed with water. The solid was dried under vacuum togive 0.98 g of solid, mp 256-258° C.

EXAMPLE 554-[(4-Methoxybenzenesulfonyl)pyridin-3-ylmethylamino]-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylicAcid, Potassium Salt

A mixture of 0.34 g (0.68 mmol) of ethyl 4-[(4-methoxybenzenesulfonyl)pyridin-3-ylmethylamino]-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylateand 0.748 ml of 1 N potassium hydroxide in 4 ml of ethanol-water (1:1)was refluxed for 24 hr. The solvent was removed under vacuum and to theresidue was added toluene. The solvent was removed under vacuum toremove the water and the residue triturated with ethyl acetate to givethe product as a solid, mp 160-167° C.

EXAMPLE 604-[(4-Methoxybenzenesulfonyl)pyridin-3-ylmethylamino]-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylicAcid, Hydroxyamide

A 1.5 g (2.459 mmol) sample of4-[(4-methoxybenzenesulfonyl)pyridin-3-ylmethylamino]-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid was dissolved in 2.70 ml of 1N KOH. The water was removed byrepeated additions and removal of toluene under vacuum to give 1.34 g ofsolid (potassium salt of the acid). A solution of 2.65 ml (5.3 mmol) ofoxalyl chloride was cooled in an ice bath and 0.389 ml ofN,N-dimethylformamide added dropwise. After 5 min. the 1.34 g of thepreviously prepared potassium salt was added and the mixture stirred for10 min. in an ice bath and then allowed to warm to room temperature(mixture A). A mixture of 0.737 g (10.6 mmol) of hydroxylaminehydrochloride and 2.21 ml (15.9 mmol) of triethyamine in 9.39 ml oftetrahydrofuran and 2.45 ml of water was chilled in an ice bath (mixtureB). The mixture A was chilled in an ice bath and added to the chilledand stirred mixture B. The mixture of A and B was stirred at 0° C. for10 min and allowed to warm to room temperature and stir overnight. Thesolvent was removed under vacuum and the residue diluted with H₂O,acidified with 2 N citric acid and extracted with two 30-ml portions ofCH₂Cl₂. The aqueous layer was neutrallized with solid NaHCO₃ to bringthe pH to 7. The solid which precipitated was filtered and washed withH₂O to give 0.610 g of product as a solid, mp. 202-204° C. The CH₂Cl₂extract was extracted with 2 N citric acid and the aqueous layerneutrallized with solid NaHCO₃. The precipitated solid was filtered offand washed with water to give 0.226 g of product, mp 196-198° C. (massspectrum (ES) 483.5 (M+1).

EXAMPLE 614-[(4-Methoxybenzenesulfonyl)pyridin-3-ylmethylamino]-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylicAcid, Hydroxyamide Hydrochloride

To a solution of 0.610 g (1.265 mmol) of4-[(4-methoxybenenzenesulfonyl)pyridin-3-ylmethylamino]-1,3-dimethyl-5-carboxylicacid, hydroxyamide in 40 ml of CH₂Cl₂-methanol (1:1) cooled to 10° C.was added dropwise 1.51 ml of 1M hydrogen chloride in diethyl ether. Themixture was stirred at 10° C. for 10 min. and allowed to warm to roomtemperature for 1 hr. The solvent was removed under vacuum and toluene(2 ml) added twice and removed under vacuum after each addition. Theresidual solid was dried under vacuum to give 0.641 g of product as asolid, m.p. 170°-174° C.

EXAMPLE 624-[Benzyl-(4-methoxybenzenesulfonyl)amino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylicAcid, Hydroxyamide

Following the procedure of Example 49, the product of Example 47 isreacted with benzyl-(4-methoxybenzenesulfonyl)amine and sodium hydrideto provide ethyl4-[benzyl-(4-methoxybenzenesulfonyl)amino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate.m.p. 124°-126° C.

Following the procedure of Example 50, the above ester is hydrolyzed toprovide4-[benzyl-(4-methoxybenzenesulfonyl)amino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid. m.p. 108°-110° C.

Following the procedure of Example 52, the carboxylic acid is convertedinto the corresponding hydroxamic acid,4-[benzyl-(4-methoxybenzenesulfonyl)amino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid, hydroxyamide. m.p. 152°-154° C.

EXAMPLE 634-[(4-Methoxybenzenesulfonyl)pyridin-3-ylmethylamino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylicAcid, Hydroxyamide

Following the procedure of Example 53, the product of Example 47 isreacted with (4-methoxybenzenesulfonyl) (3-pyridinylmethyl) amine andsodium hydride to provide ethyl4-[(4-methoxybenzenesulfonyl)pyridin-3-ylmethylamino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate.m.p. 89°-91° C.

Following the procedure of Example 54, the above ester is hydrolyzed toprovide4-[(4-methoxybenzenesulfonyl)pyridin-3-ylmethylamino]-1-phenyl-1H-pyrazolo[3,4b]pyridine-5-carboxylicacid. m.p. 136°-138° C.

Following the procedure of Example 60, the carboxylic acid is convertedinto the corresponding hydroxamic acid,4-[(4-methoxybenzenesulfonyl)pyridin-3-ylmethylamino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid, hydroxyamide. m.p. 114° C.(dec).

EXAMPLE 644-[(4-Methoxybenzenesulfonyl)pyridin-3-ylmethylamino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylicAcid, Hydroxyamide, Hydrochloride

Following the procedure of Example 61, the product of Example 63 isconverted into the corresponding hydrochloride salt. m.p. 161° C.(dec).

EXAMPLE 65 Ethyl4-chloro-1-phenyl-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

Following the procedure of Example 45, starting with1-phenyl-3-methyl-5-aminopyrazole,diethyl{[(1-phenyl-3-methyl-5-pyrazolyl)amino]methylene}malonate isobtained. m.p. 70°-72° C.

Following the procedure of Example 46, the methylene malonate isconverted into ethyl4-hydroxy-1-phenyl-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate.m.p. 132°-134° C.

Following the procedure of Example 47, the hydroxy-ester is convertedinto the chloro-ester,ethyl-4-chloro-1-phenyl-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate.m.p. 108°-110° C.

EXAMPLE 664-[Benzyl-(4-methoxybenzenesulfonyl)amino]-1-phenyl-3-methyl-1H-pyrazolo[3,4b]pyridine-5-carboxylicAcid, Hydroxyamide

Following the procedure of Example 49, the product of Example 65 isreacted with benzyl-(4-methoxybenzenesulfonyl)amine and sodium hydrideto provide ethyl4-[benzyl-(4-methoxybenzenesulfonyl)amino]-1-phenyl-3-methyl-1H-pyrazolo[3,4b]pyridine-5-carboxylate.m.p. 164°-166° C.

Following the procedure of Example 50, the above ester is hydrolyzed toprovide4-[benzyl-(4-methoxybenzenesulfonyl)amino]-1-phenyl-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid. m.p. 246°-248° C.

Following the procedure of Example 52, the carboxylic acid is convertedinto the corresponding hydroxamic acid,4-[benzyl-(4-methoxybenzenesulfonyl)amino]-1-phenyl-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid, hydroxyamide. m.p. 207°-210° C.

EXAMPLE 674-[(4-Methoxybenzenesulfonyl)pyridin-3-ylmethylamino]-1phenyl-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylicAcid, Hydroxyamide

Following the procedure of Example 53, the product of Example 65 isreacted with (4-methoxybenzenesulfonyl) (3-pyridinylmethyl) amine andsodium hydride to provideethyl-4-[(4-methoxybenzenesulfonyl)pyridin-3-ylmethylamino]-1-phenyl-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate.m.p. 148°-150° C.

Following the procedure of Example 54, the above ester is hydrolyzed toprovide4-[(4-methoxybenzenesulfonyl)pyridin-3-ylmethylamino]-1-phenyl-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid. m.p. 235°-236° C.

Following the procedure of Example 60, the carboxylic acid is convertedinto the corresponding hydroxamic acid,4-[(4-methoxybenzenesulfonyl)pyridin-3-ylmethylamino]-1-phenyl-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid, hydroxyamide. m.p. 192°-194° C.

EXAMPLE 68 4-[(4-Methoxybenzenesulfonyl)pyridin-3-ylmethylamino]-1phenyl-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic Acid, Hydroxyamide,Hydrochloride

Following the procedure of Example 61, the product of Example 67 isconverted into the corresponding hydrochloride salt. m.p. 225°-226° C.

EXAMPLE 694-[(4-Methoxybenzenesulfonyl)pyridin-2-ylmethylamino]-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylicAcid, Hydroxyamide

Following procedures described in Examples 45-68 for the preparation ofthe(substituted-4-amino)1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid, hydroxyamides, the title compound may be prepared.

EXAMPLE 704-[(4-Methoxybenzenesulfonyl)pyridin-4-ylmethylamino]-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylicAcid, Hydroxyamide

Following procedures described in Examples 45-68 for the preparation ofthe(substituted-4-amino)1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid, hydroxyamides, the title compound may be prepared.

EXAMPLE 714-[(4-Methoxybenzenesulfonyl)pyridin-3-ylmethylamino]-1-isopropyl-1H-pyrazolo[3,4-b]pyridin-5-carboxylicAcid, Hydroxyamide

Following procedures described in Examples 45-68 for the preparation ofthe(substituted-4-amino)1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid, hydroxyamides, the title compound may be prepared.

EXAMPLE 724-[(4-Methoxybenzenesulfonyl)pyridin-3-ylmethylamino]-1-benzyl-1H-pyrazolo[3,4-b]pyridin-5-carboxylicAcid, Hydroxyamide

Following procedures described in Examples 45-68 for the preparation ofthe(substituted-4-amino)1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid, hydroxyamides, the title compound may be prepared.

EXAMPLE 73 4-[(4-Methoxybenzenesulfonyl)amino]-1-benzyl-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic Acid, Hydroxyamide

Following procedures described in Examples 45-68 for the preparation ofthe(substituted-4-amino)1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid, hydroxyamides, the title compound may be prepared.

EXAMPLE 744-[(4-Methoxybenzenesulfonyl)2-thienylmethylamino]-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylicAcid, Hydroxyamide

Following procedures described in Examples 45-68 for the preparation ofthe(substituted-4-amino)1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid, hydroxyamides, the title compound may be prepared.

EXAMPLE 754-[(4-Methoxybenzenesulfonyl)-3-thienylmethylamino]-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylicAcid, Hydroxyamide

Following procedures described in Examples 45-68 for the preparation ofthe(substituted-4-amino)1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid, hydroxyamides, the title compound may be prepared.

EXAMPLE 764-[(4-Methoxybenzenesulfonyl)pyridin-3-ylmethylamino]-1-(2,4-dimethoxyphenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylicAcid, Hydroxyamide

Following procedures described in Examples 45-68 for the preparation ofthe(substituted-4-amino)1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid, hydroxyamides, the title compound may be prepared.

EXAMPLE 774-[(4-Methoxybenzenesulfonyl)pyridin-3-ylmethylamino]-1-(2-methoxyphenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylicAcid, Hydroxyamide

Following procedures described in Examples 45-68 for the preparation ofthe(substituted-4-amino)1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid, hydroxyamides, the title compound may be prepared.

EXAMPLE 784-{Methyl-[4-(4-pyridinyloxy)benzenesulfonyl]amino}-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylicAcid, Hydroxyamide

Following procedures described in Examples 45-68 for the preparation ofthe(substituted-4-amino)1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid, hydroxyamides, the title compound may be prepared.

EXAMPLE 794-{Methyl-[4-(phenoxybenzenesulfonyl)amino]-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylicAcid, Hydroxyamide

Following procedures described in Examples 45-68 for the preparation ofthe(substituted-4-amino)1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid, hydroxyamides, the title compound may be prepared.

EXAMPLE 804-[Methyl-(4-methoxybenzenesulfonyl)amino]-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylicAcid, Hydroxyamide

Following procedures described in Examples 45-68 for the preparation ofthe(substituted-4-amino)1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid, hydroxyamides, the title compound may be prepared.

EXAMPLE 814-[Methyl-(4-propyloxybenzenesulfonyl)amino]-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylicAcid, Hydroxyamide

Following procedures described in Examples 45-68 for the preparation ofthe(substituted-4-amino)1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid, hydroxyamides, the title compound may be prepared.

EXAMPLE 824-[(4-Methoxybenzenesulfonyl)pyridin-3-ylmethylamino]-1-methyl-3-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylicAcid, Hydroxyamide

Following procedures described in Examples 45-68 for the preparation ofthe(substituted-4-amino)1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid, hydroxyamides, the title compound may be prepared.

EXAMPLE 834-[(4-Methoxybenzenesulfonyl)pyridin-3-ylmethylamino]-1-ethyl-3-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylicAcid, Hydroxyamide

Following procedures described in Examples 45-68 for the preparation ofthe(substituted-4-amino)1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid, hydroxyamides, the title compound may be prepared.

EXAMPLE 844-[(4-Methoxybenzenesulfonyl)pyridin-3-ylmethylamino]-1-tert-butyl-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylicAcid, Hydroxyamide

Following procedures described in Examples 45-68 for the preparation ofthe(substituted-4-amino)1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid, hydroxyamides, the title compound may be prepared.

EXAMPLE 854-[(4-Methoxybenzenesulfonyl)pyridin-3-ylmethylamino]-1-methyl-3-tert-butyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylicAcid, Hydroxyamide

Following procedures described in Examples 45-68 for the preparation ofthe(substituted-4-amino)1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid, hydroxyamides, the title compound may be prepared.

EXAMPLE 864-[(4-Methoxybenzenesulfonyl)pyridin-3-ylmethylamino]-3-methylisothiazolo[5,4-b]pyridine-5-carboxylicAcid, Hydroxyamide

To a stirred mixture of 0.366 g (8.4 mmol) of sodium hydride (60% inoil) in 10 ml of dry 1-methyl-2-pyrrolidinone was added (portionwise)2.34 g (8.4 mmol) of methyl(4-methoxybenzenesulfonyl)pyridin-3-ylmethyl-amine. The mixture wasstirred at room temperature until gas evolution ceased and 1.80 g of(7.0 mmol) of ethyl4-chloro-3-methylisothiazolo[5,4-b]pyridine-5-carboxylate added. Themixture was heated at 80-90° C. for 44 hours, the solvent removed undervacuum and the residue diluted with water. The mixture was extractedwith ethyl acetate and the extract washed with 2N citric acid, H₂O, 1 NNaHCO₃, brine and dried (Na₂SO₄). The solution was filtered through athin pad of hydrous magnesium silicate and the pad washed with ethylacetate. The filtrate was concentrated to dryness to give 2.39 g ofethyl4-[(4-methoxybenzenesulfonyl)-pyridin-3-ylmethylamino]-3-methylisothiazolo[5,4-b]pyridine-5-carboxylateas a yellow solid, m.p. 142-144° C.

Anal. for C₂₃H₂₂N₄O₅S₂: Calc: C, 55.4; H, 4.5; N, 11.2. Found: C, 55.5;H, 4.3; N, 11.1.

Following the procedure of Example 54, a 2.25 g sample of the aboveester was hydrolysed with KOH to give 0.46 g of4-[(4-methoxybenzenesulfonyl)pyridin-3-ylmethylamino]-3-methylisothiazolo[5,4-b]pyridine-5-carboxylicacid as a white solid, m.p. 234-236° C.

Anal. for C₂₁H₁₈N₄O₅S₂: Calc: C, 53.6; H, 3.9; N, 11.9. Found: C, 53.5;H, 3.8; N, 11.8.

Following the procedure of Example 60, 2.0 g of the preceding compoundas the potassium salt was converted to the title compound to give 0.39 gof off-white solid, m.p. 145-149° C. The hydrochloride salt was preparedfrom 0.27 g of the hydroxyamide according to the procedure of Example 61to give 0.26 g of yellow solid, m.p. 224° C. dec.

Anal. for C₂₁H₁₉N₅O₅S₂.HCl: Calc: C, 48.3; H, 3.9; N, 13.4. Found: C,48.0; H, 3.8; N, 13.2.

EXAMPLE 874-[(4-Methoxybenzenesulfonyl)pyridin-3-ylmethylamino]-3-methylisoxazolo[5,4-b]pyridine-5-carboxylicAcid, Hydroxyamide

Following the procedure of Example 86, 1.7 g (7 mmol) of ethyl4-chloro-3-methylisoxazolo[5,4-b]pyridine-5-carboxylate was reacted with2.92 g (0.0105 mmol) of(4-methoxybenzenesulfonyl)pyridin-3-ylmethyl-amine to give 1.01 g ofethyl4-[(4-methoxy-benzenesulfonyl)pyridin-3-yl-methylamino]-3-methylisoxazolo[5,4-b]pyridine-5-carboxylateas a white solid, m.p. 128-130° C.

Anal. for C₂₃H₂₂N₄O₆S: Calc: C, 57.3; H, 4.6; N, 11.6. Found: C, 57.3;H, 4.7; N, 11.5.

A mixture of 1.01 g (2.1 mmol) of the preceding compound in 10 ml oftetrahydrofuran and 2.93 ml of 1 N NaOH was stirred at room temperatureovernight and the solvent removed. The residue was diluted with H₂O andacidified with 2N citric acid (pH 4). The solid was filtered off andwashed with H₂O to give 0.88 g of4-[(4-methoxybenzenesulfonyl)pyridin-3-ylmethylamino]-3-methylisoxazolo[5,4-b]pyridine-5-carboxylicacid as a white solid, m.p. 244-246° C.

Anal. for C₂₁H₁₈N₄O₆S: Calc: C, 55.5; H, 4.0; N, 12.3. Found: C, 55.2;H, 4.0; N, 12.2.

Following the procedure of Example 60, a 0.86 g (1.89 mmol) sample ofthe preceding compound was converted to the title compound to give 0.42g of off-white solid, m.p. 150° C. dec.

Anal. for C₂₁H₁₉N₅O₆S: Calc: C, 53.7; H, 4.1; N, 14.9. Found: C, 53.4;H, 4.5; N, 14.4.

The hydrochloride salt was prepared according to the procedure ofExample 61 from 0.25 g of the title compound to give a solid which ontrituration with ethyl acetate gave 0.27 g of off-white solid, m.p.212-215° C.

Anal. for C₂₁H₁₉N₅O₆S.HCl: Calc: C, 49.8; H, 4.0; N, 13.8. Found: C,49.4; H, 4.1; N, 14.0.

EXAMPLE 887-[(4-Methoxybenzenesulfonyl)pyridin-3-ylmethylamino]-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxylicAcid, Hydroxyamide

Following the procedure of Example 86, 1.8 (7.5 mmol) of ethyl7-chloro-2-methyl pyrazolo[1,5-a]pyrimidine-6-carboxylate was reactedwith 2.92 g (10.5 mmol) of(4-methoxybenzenesulfonyl)pyridin-3-ylmethyl-amine to give 1.64 g ofethyl7-[(4-methoxybenzenesulfonyl)pyridin-3-ylmethylamino]-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxylicacid as a yellow solid, m.p. 108-110° C.

Anal. for C₂₃H₂₃N₅O₅S: Calc: C, 57.4; H, 4-8; N, 14.5. Found: C, 54.5;H, 4.7; N, 14.4.

A mixture of 1.54 g (3.20 mmol) of the preceding compound,tetrahydrofuran (15 ml) and 4.15 ml of 1 N NaOH was stirred at roomtemperature overnight and the solvent removed under vacuum. The residuewas diluted with H₂O and extracted with diethyl ether and ethyl acetate.The aqueous layer was acidified with 2 N citric acid (pH 5) and thesolid filtered off and washed with H₂O. The solid was dried at 76° C. ina vacuum oven to give 1.03 g of7-[(4-methoxybenzenesulfonyl)pyridin-3-ylmethylamino]-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxylicacid as an off-white solid, m.p. 249-251° C.

Anal. for C₂₁H₁₉N₅O₅S: Calc: C, 55.6; H, 4.2; N, 15.4. Found: C, 55.2;H, 4.2; N, 15.6.

A mixture of 1.0 g (2.2 mmol) of the preceding compound, 3 ml ofCH₃OH.H₂O (2:1) and 2.43 ml of 1 N KOH was stirred 0.5 hours and thesolvent removed under vacuum. Toluene (10 ml) was added three times andthe solvent removed after each addition. The residue was dried in avacuum oven and following the procedure of Example 60 the potassium saltwas converted to the title compound to obtain 0.29 g of yellow solid,m.p. 185° C. dec.

Anal. for C₂₁H₂₀N₆O₅S: Calc: C, 53.8; H, 4.3; N, 17.9. Found: C, 53.9;H, 4.4; N, 17.3.

The hydrochloride salt was prepared according to the procedure ofExample 61 from 0.18 g of the title compound to give 0.22 g of yellowsolid, m.p. 170° C. dec.

Anal. for C₂₁H₂₀N₆O₅S.HCl: Calc: C, 50.0; H, 4.2; N, 16.6. Found: C,48.7; H, 4.4; N, 16.1.

EXAMPLE 894-{[4-(4-Chlorophenyloxy)benzenesulfonyl]methylamino}-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylicAcid, Hydroxyamide

To 20 ml of a 2 molar solution of methylamine in tetrahydrofuran chilledin an ice bath was added a solution of 5.16 g of4-(4-chlorophenyloxy)benzene-sulfonyl chloride in 50 ml oftetrahydrofuran and 20 ml of CH₂Cl₂. The mixture was refluxed for 2hours and the solvent removed under vacuum and the residue partitionedbetween CH₂Cl₂.H₂O (1:1). The CH₂Cl₂ layer was separated and washed with2 N citric acid, brine and dried (Na₂SO₄). The solution was filteredthrough a thin pad of hydrous magnesium silicate and the filter padwashed with CH₂Cl₂. The filtrate was concentrated to give 4.5 g ofN-methyl-4-(4-chlorophenoxy)benzene-sulfonamide as a yellow solid, m.p.80-83° C.

Following the procedure of Example 53, 1.79 g (6 mmol) of the precedingcompound was reacted with 1.29 g (5 mmol) of ethyl 4-chloro-1,3-dimethylpyrazolo[3,4b]pyridine-5-carboxylate at 80-90° C. for 48 hours to give3.12 g of solid. Chromatography on silica gel with hexane-diethyl ether(2:1) as eluent to give 1.92 g of ethyl4-{[4-(4-chlorophenyloxy)benzenesulfonyl]methylamino}-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylateas an off-white solid, m.p. 52-55° C.

Anal. for C₂₄H₂₃ClN₄O₅S: Calc: C, 56.0; H, 4.5; N, 10.9. Found: C, 55.9;H, 4.4; N, 10.6.

A mixture of 1.90 g (3.69 mmol) of the preceding ester and 4.05 ml (4.06mmol) of 1 N KOH in 15 ml of tetrahydrofuran was stirred at roomtemperature for 2 days and then 0.75 ml of 1 N KOH was added and themixture was refluxed overnight. The solvent was removed under vacuum andthe toluene (25 ml) added to the residue and removed under vacuum. Theresidue was triturated with ethyl acetate and the solid filtered anddried under vacuum to give 1.6 g of 4-{[4-(4-chlorophenyloxy)benzenesulfonyl]methylamino}-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid, potassium salt. Following the procedure of Example 52, 1.60 g ofthe preceding potassium salt was converted to the title compound toobtain 1.82 g of solid. This solid was purified on thick layer silicagel plates with 4% CH₃OH in ethyl acetate as solvent to give 0.59 g oflight yellow solid, m.p. 120° C. dec.

Anal. for C₂₂H₂₀ClN₅O₅S.H₂O: Calc: C, 51.7; H, 4.3; N, 13.7. Found: C,51.2; H, 4.0; N, 13.6.

EXAMPLE 904-{[4-(4-Chlorophenyloxy)benzenesulfonyl]methylamino}-3-methylisothiazolo[5,4-b]pyridine-5-carboxylicAcid Hydroxyamide

Following the procedure of Example 86, 1.17 g (38.5 mmol) ofN-methyl-4-(4-chlorophenoxy)benzene-sulfonamide was reacted with 0.916 g(3.57 mmol) of ethyl4-chloro-3-methylisothiazolo[5,4-b]pyridine-5-carboxylate for 33 hoursto give a solid which was triturated with ethyl acetate to give 0.99 gof ethyl4-{[4-(4-chlorophenyloxy)benzenesulfonyl]methylamino}-3-methylisothiazolo[5,4-b]pyridine-5-carboxylateas a white solid, m.p. 117-120° C.

Anal. for C₂₃H₂₀ClN₃O₅S₂: Calc: C, 53.3; H, 3.9; N, 8.1. Found: C, 53.2;H, 3.9; N, 7.8.

Following the procedure of Example 54, a mixture of 0.96 g (1.85 mmol)of the preceding compound and 2.40 ml of 1 N KOH in 15 ml oftetrahydrofuran-ethanol (2:1) was refluxed 16 hours and the solventremoved under vacuum. Toluene (25 ml) was added to the residue and thesolvent removed. The residue was triturated with ethyl acetate to give asolid which was dried under vacuum to give 0.80 g of4-{[4-(4-chlorophenyloxy)-benzenesulfonyl]methylamino)-3-methylisothiazolo[5,4-b]pyridine-5-carboxylicacid, potassium salt. Following the procedure of Example 52, 0.80 g(1.51 mmol) of the preceding compound was converted to the titlecompound to give 0.82 g of solid. This solid was chromatographed onthick layer silica gel plates with 4% CH₃OH in ethyl acetate as solventto give 0.19 g of solid which was triturated with hexane to give 0.12 gof 115° C. dec.

Anal. for C₂₁H₁₇ClN₄O₅S₂.¼ hexane: Calc: C, 51.3; H, 3.9; N, 10.6.Found: C, 51.9; H, 4.2; N, 10.4.

EXAMPLE 914-{Methyl-[4-(4-pyridinyloxy)benzenesulfonyl]amino)-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylicAcid, Hydroxyamide

A suspension of 35 g of [4-(4-pyridinyloxy)benzenesulfonyl chloridehydrochloride in 800 ml of tetrahydrofuran was added slowly to 163 ml of2 M methylamine in tetrahydrofuran. An additional 550 ml oftetrahydrofuran was added and the suspension refluxed for 3 hours. Thesolvent was removed under vacuum and the residue partitioned betweenCH₂Cl₂ and H₂O. The organic layer was separated, washed with saturatedNaHCO₃, brine and dried (Na₂SO₄). The solvent was removed to give 13.11g of N-methyl-4-(pyridin-4-yloxy)benzenesulfonamide, m.p. 125-127° C.The aqueous layer was neutralized with 1 N NaOH (solid precipitated) andextracted with CH₂Cl₂. The extract was washed with brine and dried(Na₂SO₄). The solvent was removed to give an additional 15.9 g ofN-methyl-4-(pyridin-4-yloxy)benzenesulfonamide. A 2.80 g (10.6 mmol)portion of the preceding compound was added to a stirred suspension of0.424 g (10.6 mmol) of sodium hydride (60% in oil) in 20 ml of dry1-methylpyrrolidinone. The mixture was stirred until gas evolutionceased and 2.8 g (10.0 mmol) of ethyl4-chloro-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate was addedfollowed by the addition of 20 ml of dry 1-methylpyrrolidinone. Themixture was heated at 80-90° C. for 58 hours. The solvent was removedunder vacuum and the residue extracted with ethyl acetate (100 ml) andthe extract washed with 100 ml of H₂O. The extract was stirred with 40ml of 1 N HCl for 1 hour and the aqueous layer separated and neutralized(pH 6-7) with 1 N NaHCO₃. The mixture was extracted with ethyl acetateand the extract washed with H₂O, brine and dried (Na₂SO₄). The solutionwas filtered through a thin pad of hydrous magnesium silicate and thefilter pad washed with ethyl acetate. The filtrate was concentrated todryness and the residue crystallized with ethyl acetate-hexane to give3.43 g of ethyl4-(methyl-[4-(4-pyridinyloxy)benzenesulfonyl]amino}-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylateas pale yellow crystals, m.p. 117-119° C.

Anal. for C₂₃H₂₃N₅O₅S: Calc: C, 57.4; H, 4.8; N, 14.5. Found: C, 57.3;H, 4.7; N, 14.5.

A mixture of 7.44 g (15.5 mmol) of the preceding compound and 18.54 mlof 1 N KOH in 100 ml tetrahydrofuran-ethanol (6:4) was refluxedovernight under nitrogen. The solvent was removed and toluene andethanol added and the solvent removed under vacuum. The residue wastriturated with diethyl ether, filtered and the solid dried under vacuumto give 7.57 g of the potassium salt of4-{methyl-[4-(4-pyridinyloxy)benzenesulfonyl]amino}-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid. A 0.18 g sample of the preceding compound was dissolved in H₂O andthe solution brought to pH 6 with 2 N citric acid. The precipitatedsolid was filtered, washed with H₂O and dried under vacuum to give 0.045g of4-{methyl-[4-(4-pyridinyloxy)benzenesulfonyl]amino}-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid as a white solid, m.p. 171-185° C.

Anal. for C₂₁H₁₉N₅O₅S.2 H₂O: Calc: C, 51.5; H, 4.7; N, 14.3. Found: C,51.8; H, 4.1; N, 14.2.

To a chilled (0° C.) mixture of 2.2 ml (4.4 mmol) of oxalyl chloride inCH₂Cl₂ (2 M) was added dropwise 0.308 ml (4.0 mmol) ofN,N-dimethylformamide followed by the addition of 0.982 g (2 mmol) ofthe preceding potassium salt and 10 ml of CH₂Cl₂ (Mixture A). A mixtureof 0.444 ml (8 mmol) of hydroxylamine in H₂O (50% w), 0.634 ml oftriethylamine and 3.50 ml of tetrahydrofuran was chilled and added tothe chilled Mixture A. After stirring at 0° C. for 15 min., the mixturewas stirred at room temperature overnight. The solvent was removed andthe residue partitioned between 10 ml of CH₂Cl₂ and 30 ml of H₂O. Thesolid was filtered off and suspended in H₂O. The pH of the mixture wasadjusted to pH 6-7 with 2 N citric acid, stirred, filtered and the solidwashed with H₂O and CH₂Cl₂ to give 0.47 g of4-{methyl-[4-(4-pyridinyloxy)benzenesulfonyl]amino}-1,3dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid, hydroxyamide as a white solid, m.p. 147° dec.

Anal. for C₂₁H₂₀N₆O₅S.H₂O: Calc: C, 51.8; H, 4.6; N, 17.3. Found: C,51.3; H, 4.8; N, 17.4.

To a cooled 2.2 g (4.7 mmol) sample of the preceding compound in 40 mlof CH₂Cl₂—CH₃OH (1:1) was added 5.64 ml of 1 M HCl in diethyl ether. Themixture was stirred in an ice bath for 10 min. and then at roomtemperature for 1 hour. The solvent was removed under vacuum and 25 mlof toluene added (two times) and removed under vacuum. The solid wastriturated with 20 ml of methanol to give 1.60 g of the product of theExample as a white solid, m.p. 197-200° C.

Anal. for C₂₁H₂₀N₆O₅S.HCl.H₂O: Calc: C, 48.2; H, 4.4; N, 16.1. Found: C,47.7; H, 4.7; N, 15.9.

EXAMPLE 924-{Methyl-[4-(4-pyridinyloxy)benzenesulfonyl]amino}-3-methylisothiazolo[5,4-b]pyridine-5-carboxylicAcid, Hydroxyamide

Following the procedure of Example 86, 1.28 g (5 mmol) of ethyl4-chloro-3-methylisothiazolo[5,4-b]pyridine-5-carboxylate was reactedwith 1.4 g (5.3 mmol) of N-methyl-4-(pyridin-4-yloxy)benzenesulfonamideto give 2.78 g of an oil. This oil was dissolved in 10 ml of ethylacetate and 13 ml of 1 N HCl added. The organic layer was separated. Theaqueous layer was brought to pH 6 with 1 N NaOH and extracted with 40 mlof CH₂Cl₂. The CH₂Cl₂ extract was washed with brine and dried (Na₂SO₄).The solvent was removed to give 1.69 g of solid which waschromatographed on silica gel with ethyl acetate as solvent to give 0.95g of ethyl4-{methyl-[4-(4-pyridinyloxy)benzene-sulfonyl]amino}-3-methylisothiazolo[5,4-b]pyridine-5-carboxylateas a yellow solid, m.p. 57-60° C.

Anal. for C₂₂H₂₀N₄O₅S₂: Calc: C, 54.5; H, 4.2; N, 11.6. Found: C, 54.4;H, 4.1; N, 11.2.

Following the procedure of Example 50, a mixture of 0.95 g of thepreceding ester and 2.8 ml of 1 N KOH in 2.5 ml of tetrahydrofuran and25 ml of ethanol was refluxed 24 hours and the solvent removed undervacuum to give 1.0 g of solid. Following the procedure of Example 91, a0.82 g sample of the resulting potassium salt was reacted withhydroxylamine to give 0.78 g of solid. Chromatography on thick layersilica gel plates with ethyl acetate-CH₃OH (85:15) as solvent gave 0.22g of4-{methyl-[4-(4-pyridinyloxy)benzenesulfonyl]amino}-3-methylisothiazolo[5,4-b]pyridine-5-carboxylicacid, hydroxyamide as an off-white solid, m.p. 146° C. dec.

Anal. for C₂₀H₁₇N₅O₅S₂.½ H₂O: Calc: C, 50.0; H, 3.8; N, 14.6. Found: C,49.7; H, 4.0; N, 13.8.

To a solution of 0.20 g of the preceding compound in 3.4 ml ofCH₂Cl₂—CH₃OH (1:1) was added 0.508 ml of 1 N HCl in diethyl ether. Thesolvent was removed under vacuum and the solid dried 20 hours undervacuum to give the hydrochloride salt of the title compound as anoff-white solid, m.p. 186° C. dec.

Anal. for C₂₀H₁₇N₅O₅S₂.HCl.H₂O: Calc: C, 45.6; H, 3.8; N, 13.3. Found:C, 45.6; H, 4.1; N, 12.7.

EXAMPLE 934-(Methyl-[4-(4-pyridinyloxy)benzenesulfonyl]amino}-1-methyl-3-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylicAcid, Hydroxyamide

Following the procedure described in Example 91, 1.45 g (5.5 mmol) ofN-methyl-4-(pyridinyl-4-oxy)benzenesulfonamide was reacted with 1.58 g(5 mmol) of ethyl4-chloro-1-methyl-3-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate in20 ml of 1-methyl-pyrrolidinone to give 1.62 g of ethyl4-{methyl-[4-(4-pyridinyloxy)benzenesulfonyl]-amino}-1-methyl-3-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylateas an off-white solid, m.p. 128-131° C.

Anal. for C₂₈H₂₅N₅O₅S: Calc: C, 61.9; H, 4.6; N, 12.9. Found: C, 61.7;H, 4.7; N, 12.8.

A mixture of 1.60 g (2.94 mmol) of the preceding compound and 3.53 ml of1 N KOH in 8 ml of tetrahydrofuran-ethanol (1:1) was refluxed overnightand the solvent removed. The residue was triturated with diethyl etherto give 1.62 g of potassium4-{methyl-[4-(4-pyridinyloxy)benzenesulfonyl]amino}-1-methyl-3-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylateas solid.

Following the procedure of Example 91, a 1.47 g (2.66 mmol) sample ofthe preceding compound was reacted with hydroxylamine to give 0.49 g ofsolid. This solid (0.45 g) was dissolved in 15 ml of CH₂Cl₂—CH₃OH (1:1)and to the chilled solution was added 2.26 ml of 1 N HCl in diethylether. The mixture was stirred at room temperature for 1 hour and thesolvent removed to give the hydrochloride salt of the title compound asan off-white solid, m.p. 195° C. dec.

Anal. for C₂₆H₂₂N₆O₅S.HCl.H₂O: Calc: C, 53.4; H, 5.0; N, 14.4. Found: C,53.2; H, 4.3; N, 14.3.

EXAMPLE 944-{Methyl-[4-(4-pyridinyloxy)benzenesulfonyl]amino}-3-methylisoxazolo[5,4-b]pyridine-5-carboxylicAcid, Hydroxyamide

Following the procedure of Example 91, 1.45 g (5.5 mmol) ofN-methyl-4-(pyridinyl-4-oxy)benzenesulfonamide was reacted with 1.20 g(5 mmol) of ethyl4-chloro-3-methylisoxazolo[5,4-b]pyridine-5-carboxylate to give 1.29 gof ethyl4-{methyl-[4-(4-pyridinyloxy)-benzenesulfonyl]amino}-3-methylisoxazolo[5,4-b]pyridine-5-carboxylateas an off-white solid, m.p. 155-157° C.

Anal. for C₂₂H₂₀N₄O₆S.½ H₂O: Calc: C, 55.3; H, 4.4; N, 11.7. Found: C,55.2; H, 4.3; N, 11.6.

A mixture of 1.84 g (3.92 mmol) of the preceding ester and 4.71 ml of 1N KOH in 10 ml of tetrahydrofuran-ethanol (1:1) was refluxed overnightand the solvent removed under vacuum. The residue was triturated withdiethyl ether and filtered to give 1.59 g of potassium4-{methyl-[4-(4-pyridinyloxy)benzene-sulfonyl]amino}-3-methylisoxazolo[5,4b]pyridine-5-carboxylateas a pale yellow solid. Following the procedure of Example 91, thepreceding potassium salt (1.45 g) was reacted with hydroxylamine to givea solid. The solid was partitioned between 30 ml of CH₂Cl₂ and 30 ml ofH₂O and filtered. The CH₂Cl₂ layer was stirred with 2 N citric acid(aqueous phase-pH 6). The solid which precipitated was filtered off andsuspended in H₂O. The aqueous suspension was adjusted to pH 7 with 1 NNaHCO₃ and filtered. The solid was again suspended in H₂O and the pH ofthe aqueous suspension adjusted to pH 6 with 2 N citric acid. Themixture was stirred and filtered to give 0.66 g of4-{methyl-[4-(4-pyridinyl-oxy)benzenesulfonyl]amino}-3-methylisoxazolo[5,4-b]pyridine-5-carboxylicacid, hydroxyamide, m.p. 141° C. dec.

Anal. for C₂₆H₂₂N₆O₅S.H₂O: Calc: C, 58.9; H, 4.4; N, 15.3. Found: C,56.3; H, 4.3; N, 15.2.

To a chilled solution of 0.569 g (1.25 mmol) of the precedinghydroxyamide in 10 ml of CH₂Cl₂—CH₃OH (1:1) was added 1.50 ml of 1 N HClin diethyl ether. The mixture was stirred at room temperature for 1 hourand the solvent removed to give 0.582 g of the hydrochloride salt of thetitle compound as a light brown solid, m.p. 170° C. dec.

Anal. for C₂₀H₁₇N₅O₆S.HCl.H₂O: Calc: C, 47.1; H, 4.0; N, 13.7. Found: C,47.2; H, 4.5; N, 13.2.

EXAMPLE 957-{Methyl-[4-(4-pyridinyloxy)benzenesulfonyl]amino}-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxylicAcid, Hydroxyamide

Following the procedure of Example 86, 1.19 g (5 mmol) of ethyl7-chloro-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxylate was reactedwith 1.45 g (5.5 mmol) of N-methyl-4-(pyridinyl-4oxy)benzenesulfonamide(as the sodium salt) in 20 ml of 1-methylpyrrolidinone at 80-90° C. for66 hours. The solvent was removed and the residue partitioned between 30ml of ethyl acetate and 30 ml of H₂O. The organic layer was separted andstirred with 30 ml of 1 N HCl for 1 hour and filtered. The aqueous layerwas separated and the pH adjusted to pH 6 with saturated NaHCO₃solution. The mixture was extracted with ethyl acetate and the extractwashed with brine and dried (Na₂SO₄). The solution was filtered througha thin pad of hydrous magnesium silicate and the filter pad washed withethyl acetate. The filtrate was concentrated to dryness and the solidsuspended in 50 ml of H₂O and the pH of the stirred suspension adjustedto pH 7 with 1 N NaHCO₃. The mixture was extracted with ethyl acetateand the extract washed with brine and dried (Na₂SO₄). The solution wasfiltered through a thin pad of hydrous magnesium silicate and thefiltrate concentrated to dryness to give 1.35 g of ethyl7-{methyl-[4-(4-pyridinyloxy)-benzenesulfonyl]amino}-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxylateas a yellow solid, m.p. 139-144° C.

Anal. for C₂₂H₂₁N₄O₅S: Calc: C, 56.5; H, 4.5; N, 15.0. Pound: C, 56.8;H, 4.6; N, 14.9.

A mixture of 1.25 g (2.67 mmol) of the preceding ester and 3.21 ml of 1N KOH in 15 ml of tetrahydrofuran was stirred at room temperatureovernight. The mixture was filtered and the solid washed with diethylether and ethyl acetate to give 0.5 g of potassium7-{methyl-[4-(4-pyridinyloxy)benzene-sulfonyl]amino}-2-methylpyrazolo[1,5-a]pyrimidine-6carboxylate.A 0.15 g sample of the preceding compound was dissolved in water and thepH adjusted to pH 6 with 2 N citric acid. The mixture was filtered togive 0.12 g of7-{methyl-[4(4-pyridinyloxy)benzenesulfonyl]amino}-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxylicacid as a white solid, m.p. 246-248° C.

Anal. for C₂₀H₁₇N₅O₅S: Calc: C, 54.7; H, 3.9; N, 15.9. Found: C, 54.2;H, 4.1; N, 16.4.

Following the procedures of Example 91, the title compound is preparedfrom the carboxylic acid described above.

EXAMPLE 964-{Methyl-[4-(4-pyridinyloxy)benzenesulfonyl]amino}-7-methyl-1,8-naphthyridine-3-carboxylicAcid, Hydroxyamide

A mixture of 10.8 g (0.1 M) of 2-amino-6-methylpyridine and 23.78 g(0.12 M) of diethyl ethoxymethylenemalonate was heated in an oil bath(preheated to 90° C.) for 1 hr. The mixture was cooled to roomtemperature and the solid was recrystallized from 100 ml of ethanol togive 26.38 g of 2-(2,2-dicarbethoxy-1-vinylamino)-6-methylpyridine, m.p.102-104° C. Reported m.p. 107-108° C. (U.S. Pat. No. 4,166,817 issuedSep. 4, 1979). A solution of 20.79 g of the preceding compound in 40 mlof Dowtherm (heated to 80° C.) was dropped into 100 ml of Dowtherm whichhad been preheated to 258° C. The temperature of the mixture dropped to200° C. and after the temperature returned to 250° C. (10 min), themixture was heated at 250° C. for 30 min. The mixture was immediatelycooled to room temperature and allowed to stand overnight. The mixturewas filtered and the solid washed with hexane and CH₂Cl₂ to give 4.24 gof ethyl 4-hydroxy-7-methyl-1,8-naphthyridine-3-carboxylate as a brownsolid.

A mixture of 4.2 g (0.018 M) of the preceding compound and 45 ml ofPOCl₃ (0.48 M) was heated at 70-80° C. for 4 hours. The solution wasconcentrated under vacuum and the residue poured onto crushed ice. Theresulting mixture was neutralized with 5 N NaOH to pH 6 and extractedwith diethyl ether (3×250 ml). The extract was washed with brine anddried over Na₂SO₄). The solvent was removed under vacuum to give 2.24 gof ethyl 4-chloro-7-methyl-1,8-naphthyridine-3-carboxylate as a yellowsolid, m.p. 72-74° C.: reported m.p. 92-93° C. (dec) (U.S. Pat. No.4,166,817).

To a mixture (under nitrogen) of 0.22 g (5.5 mmol) of NaH (60% in oil)in 20 ml of 1-methylpyrrolidinone was added 1.45 g (5.5 mmol) ofN-methyl-4-(pyridin-4-yloxy)benzenesulfonamide. After gas evolutionceased, 1.25 g (5 mmol) of ethyl4-chloro-7-methyl-1,8-naphthyridine-3-carboxylate was added. The mixturewas heated at 80-90° C. for 60 hrs and the solvent removed under vacuum.The residue was partitioned between H₂O and ethyl acetate and themixture filtered through diatomaceous earth. The organic layer of thefiltrate was separated and washed with H₂O and dried (Na₂SO₄). Thesolution was filtered through a thin pad of hydrous magnesium silicateand the filtrate concentrated under vacuum to give 0.97 g of a brownsolid (mass spectrum 265 (75%); 479 (25%). The product (mass spectrum(M+H) 479) is separated by chromatography on silica gel and followingthe procedure of Example 91 is converted to the title compound.

EXAMPLE 977-{Methyl-[4-(4-pyridinyloxy)benzenesulfonyl]amino}-2,3-dimethylimidazo[4,5-b]pyridine-6-carboxylicAcid, Hydroxyamide

Following the general procedure described in J. Chem. Soc. Perkin Trans.1, 2789 (1992) a mixture of 1,2-dimethyl-5-nitroimidazole (8.46 g; 0.06M), diethyl ethoxymethylenemalonate (13.08 g; 0.06 M) and 2.11 g of 5%Pd on carbon in 135 ml of dioxane was reduced in a Parr Hydrogenator at35 to 40 psi of hydrogen for 29 hours. The mixture was filtered throughdiatomaceous earth and the solvent removed to give a brown oil. This oilwas dissolved in 100 ml of 2 N HCl and the pH adjusted to pH 5 with 10 NNaOH. The mixture was extracted twice with 100 ml of ethyl acetate(extract discarded). The pH was adjusted to pH 7 and extracted with 150ml of ethyl acetate and then the pH was adjusted to pH 9 and againextracted twice with 150 ml of ethyl acetate. The pH 7 and pH 9 extractswere combined and washed with brine and dried over Na₂SO₄. The solutionwas filtered through a thin pad of hydrous magnesium silicate and thefiltrate concentrated to dryness to give 7.61 g of5-[2,2-bis(ethoxycarbonyl)-1-vinylamino]-1,2-dimethylimidazole (diethyl[(1,2-dimethylimidazol-5-yl)aminomethylene]malonate) as a brown oil.

A mixture of the preceding compound (7.9 g) and 35 ml of POCl₃ wasrefluxed for 7 hours under nitrogen and then concentrated under vacuum.The black residue was poured onto crushed ice (with stirring) and themixture brought to pH 5 with 5 N NaOH. The mixture was extracted with150 ml of ethyl acetate, 200 ml of diethyl ether and 200 ml of CH₂Cl₂.Each extract was washed with 1 N NaHCO₃, brine and dried (Na₂SO₄). Thesolutions were combined and filtered through a thin pad of hydrousmagnesium silicate. The filtrate was concentrated to dryness undervacuum to give 4.1 g of ethyl7-chloro-2,3-dimethylimidazo[4,5-b]pyridine-6-carboxylate as a tansolid, m.p. 85-90° C. A sample crystallized from diethyl ether gavecrystals, m.p. 117-119° C.,

Anal. for C₁₁H₁₂ClN₃O₂.½ H₂O: Calc: C, 48.8; H, 4.6; N, 15.9. Found: C,50.3; H, 5.6; N, 16.0.

Following the procedure of Example 91, a 0.759 g (3 mmol) portion of thepreceding ester was heated at 80-90° C. in 14 ml of1-methylpyrrolidinone with the sodium salt ofN-methyl-4-(pyridin-4-yloxy)benzenesulfonamide [from 0.871 g; 3.3 mmolof N-methyl-4-(pyridin-yloxy)benzenesulfonamide and 79.2 mg (3.3 mmol)of NaH (60% in oil)]. The mixture was heated for 2.5 days at 80-90° C.and 3 hrs at 100° C. and then the solvent was removed under vacuum. Theresidue was extracted with ethyl acetate and the extract washed withH₂O. The organic layer was stirred with 1 N HCl (30 ml) for 0.5 hour andthe aqueous layer separated and brought to pH 6 with 5 N NaOH. Themixture was extracted with ethyl acetate and the extract dried overNa₂SO₄. The solvent was removed under vacuum to give 1.0 g of a brownoil which contained the product ethyl7-{methyl-[4-(4-pyridinyloxy)benzenesulfonylamino}-2,3-dimethylimidazo[4,5-b]pyridine-6-carboxylate;mass spectrum (ES) 479.1 (M+H). Following the procedure of Example 91,the preceding compound is converted to the title compound.

EXAMPLE 98 2-Methyl-4-{methyl-[4-(4-pyridinyloxy)benzenesulfonyl]amino}thieno[3,4-b]pyridine-3-carboxylic Acid,Hydroxyamide

A mixture of 10.0 g (63.6 mmol) of methyl3-aminothiophene-4-carboxylate, 10.1 g (63.6 mmol) of ethyl(trans)-3-ethoxycrotonate and 40 mg of p-toluenesulfonic acid,monohydrate in 50 ml of p-xylenes was refluxed overnight and the solventremoved under vacuum. To the residue was added 20 ml of p-xylenes, and23.7 ml of NaOC₂H₅ (21% by wt) (63.6 mmol) in ethanol and the mixturerefluxed for 3 hrs. The solvent was removed, the residue diluted withH₂O and the pH adjusted to pH 4 with 1 N HCl. The precipitate wasfiltered, washed with water and ethyl acetate to give 4.95 g of4-hydroxy-2-methyl-thieno[3,4-b]pyridine-3-carboxylic acid as a brownsolid.

The preceding compound (1.4 g) was dissolved in 10 ml of dry methanoland HCl gas bubbled into the solution for 10 min. The solution wasstirred overnight at room temperature and the solvent removed undervacuum. The residue was dissolved in ethyl acetate and the solutionwashed with saturated NaHCO₃, brine and dried (Na₂SO₄). The solvent wasremoved to give a solid which was triturated with ethyl acetate. Themixture was cooled and filtered to give 0.765 g of methyl4-chloro-2-methylthieno[3,4-b]pyridine-3-carboxylate as a yellow solid.

Following the procedure of Example 91, the preceding compound isconverted to the title compound.

EXAMPLE 995-Methyl-7-{methyl-[4-(4-pyridinyloxy)benzenesulfonyl]amino}thieno[3,2-b]pyridine-6-carboxylicAcid, Hydroxyamide

Following the procedure described in J. Med. Chem. 33, 2640 (1990), amixture of 10 g (63.6 mmol) of methyl 3-aminothiophene-2-carboxylate(10.1 g) (63.6 mmol) of ethyl (trans)-3-ethoxycrotonate and 40 mg ofp-toluenesulfonic acid monohydrate in 80 ml of xylene was refluxedovernight. The solvent was removed under vacuum and the residuedissolved in ethyl acetate. The solution was washed with H₂O, 2 N citricacid, 1 N NaHCO₃, brine and dried (Na₂SO₄). The solid 16 g waschromatographed on silica gel with hexaneethyl acetate (5:1) to give6.65 g of ethyl 3-[(2-methyoxycarbonyl-3-thienyl)amino]crotonate as ayellow oil. To a sample of 0.269 g (1 mmol) of the preceding compound in3.5 ml of xylenes (chilled in an ice bath) was added 44 mg (1.1 mmol) ofNaH (60% in oil). The mixture was refluxed for 3 hours and the solventremoved. The residue diluted with water and extracted with ethylacetate. The aqueous layer was acidified (1 N HCl) to pH 4 and themixture extracted with ethyl acetate. The extract was washed with brine,dried over Na₂SO₄ and the solvent removed to give 190 mg of a mixture(1:1) of methyl 7-hydroxy-5-methylthieno[3,2-b]pyridine-6-carboxylateand ethyl 7-hydroxy-5-methylthieno[3,2-b]pyridine-6-carboxylate as asolid. The preceding ethyl ester was prepared in the following manner.

A mixture of 5.0 g (31.8 mmol) of methyl 3-aminothiophene-2-carboxylate,5.03 g (31.8 mmol) of ethyl (trans)-3-ethoxycrotonate and 20 mg ofp-toluenesulfonic acid monohydrate in 50 ml of p-xylenes was refluxed 1hour and allowed to stand 2 days at room temperature. The mixture wasconcentrated under vacuum and then cooled (ice bath). To the solutionwas added 12.4 ml of a solution of sodium ethoxide (21% by wt) inethanol. The mixture was refluxed for 2 hours and the solvent removed.The residue was partitioned between H₂O and diethyl ether and the H₂Olayer separated and acidified to pH 4 with 1 N HCl. The mixture wasextracted with ethyl acetate and the extract washed with brine and dried(Na₂SO₄). The solvent was removed to give 2.2 g of brown solid. Thesolid was triturated with ethyl acetate, chilled and filtered to give1.0 g of ethyl 7-hydroxy-5-methylthieno[3,2-b]pyridine-6-carboxylate asa light tan solid (mass spectrum (ES) 238 (M+H).

A mixture of the preceding compound (0.985 g) and 4 ml of POCl₃ wasrefluxed 2 hours and the mixture poured onto crushed ice. The mixturewas extracted with ethyl acetate and the extract concentrated todryness. The residue was dissolved in CH₂Cl₂ and the solution washedwith H₂O and dried over Na₂SO₄. The solution was filtered through a thinpad of hydrous magnesium silicate and the filtrate concentrated todryness to give 0.62 g of ethyl7-chloro-5-methylthieno[3,2-b]pyridine-6-carboxylate as a yellow oil;thin layer chromatography on silica gel; Rf=0.9; ethyl acetate-hexane(1:1).

Following the procedure of Example 86, the preceding compound is reactedwith N-methyl-4-(pyridin-4-yloxy)benzenesulfonamide to give ethyl5-methyl-7-{methyl-[4-(4-pyridinyloxy)benzenesulfonyl]amino}thieno[3,2-b]pyridine-6-carboxylate.As described for Example 91, the preceding compound is converted to thetitle compound.

Representative compounds of this invention were evaluated as inhibitorsof the enzymes MMP-1, MMP-9, MMP-13 and TNF-α converting enzyme (TACE).The standard pharmacological test procedures used, and results obtainedwhich establish this biological profile are shown below.

Test Procedures for Measuring MMP-1, MMP-9, and MMP-13 Inhibition

These standard pharmacological test procedures are based on the cleavageof a thiopeptide substrates such asAc-Pro-Leu-Gly(2-mercapto-4-methyl-pentanoyl)-Leu-Gly-OEt by the matrixmetalloproteinases MMP-1, MMP-13 (collagenases) or MMP-9 (gelatinase),which results in the release of a substrate product that reactscolorimetrically with DTNB (5,5′-dithiobis(2-nitro-benzoic acid)). Theenzyme activity is measured by the rate of the color increase. Thethiopeptide substrate is made up fresh as a 20 mM stock in 100% DMSO andthe DTNB is dissolved in 100% DMSO as a 100 mM stock and stored in thedark at room temperature. Both the substrate and DTNB are dilutedtogether to 1 mM with substrate buffer (50 mM HEPES pH 7.5, 5 mM CaCl₂)before use. The stock of enzyme is diluted with buffer (50 mM HEPES, pH7.5, 5 mM CaCl₂, 0.02% Brij) to the desired final concentration. Thebuffer, enzyme, vehicle or inhibitor, and DTNB/substrate are added inthis order to a 96 well plate (total reaction volume of 200 μl) and theincrease in color is monitored spectrophotometrically for 5 minutes at405 nm on a plate reader and the increase in color over time is plottedas a linear line.

Alternatively, a fluorescent peptide substrate is used. In this testprocedure, the peptide substrate contains a fluorescent group and aquenching group. Upon cleavage of the substrate by an MMP, thefluorescence that is generated is quantitated on the fluorescence platereader. The assay is run in HCBC assay buffer (50 mM HEPES, pH 7.0, 5 mMCa⁺², 0.02% Brij, 0.5% Cysteine), with human recombinant MMP-1, MMP-9,or MMP-13. The substrate is dissolved in methanol and stored frozen in 1mM aliquots. For the assay, substrate and enzymes are diluted in HCBCbuffer to the desired concentrations. Compounds are added to the 96 wellplate containing enzyme and the reaction is started by the addition ofsubstrate. The reaction is read (excitation 340 nm, emission 444 nm) for10 min. and the increase in fluorescence over time is plotted as alinear line.

For either the thiopeptide or fluorescent peptide test procedures, theslope of the line is calculated and represents the reaction rate. Thelinearity of the reaction rate is confirmed (r²>0.85). The mean (x±sem)of the control rate is calculated and compared for statisticalsignificance (p<0.05) with drug-treated rates using Dunnett's multiplecomparison test. Dose-response relationships can be generated usingmultiple doses of drug and IC₅₀ values with 95% CI are estimated usinglinear regression.

In vivo MMP Inhibition Test Procedure

A 2 cm piece of dialysis tubing (molecular weight cut-off 12-14,000, 10mm flat width) containing matrix metalloproteinase enzyme (stromelysin,collagenase or gelatinase in 0.5 mL of buffer) is implanted either ip orsc (in the back) of a rat (Sprague-Dawley, 150-200 g) or mouse (CD-1,25-50 g) under anesthesia. Drugs are administered PO, IP, SC or IVthrough a canula in the jugular vein. Drugs are administered in a dosevolume of 0.1 to 0.25 mL/animal. Contents of the dialysis tubing iscollected and enzyme activity assayed.

Enzyme reaction rates for each dialysis tube are calculated. Tubes fromat least 3 different animals are used to calculate the mean±sem.Statistical significance (p<0.05) of vehicle-treated animals versusdrug-treated animals is determined by analysis of variance. (Agents andActions 21: 331, 1987).

Test Procedure for Measuring TACE Inhibition

Using 96-well black microtiter plates, each well receives a solutioncomposed of 10 μL TACE (final concentration 1 μg/mL), 70 μL Tris buffer,pH 7.4 containing 10% glycerol (final concentration 10 mM), and 10 μL oftest compound solution in DMSO (final concentration 1 μM, DMSOconcentration <1%) and incubated for 10 minutes at room temperature. Thereaction is initiated by addition of a fluorescent peptidyl substrate(final concentration 100 μM) to each well and then shaking on a shakerfor 5 sec.

The reaction is read (excitation 340 nm, emission 420 nm) for 10 min.and the increase in fluorescence over time is plotted as a linear line.The slope of the line is calculated and represents the reaction rate.

The linearity of the reaction rate is confirmed (r²>0.85). The mean(x±sem) of the control rate is calculated and compared for statisticalsignificance (p<0.05) with drug-treated rates using Dunnett's multiplecomparison test. Dose-response relationships can be generate usingmultiple doses of drug and IC₅₀ values with 95% CI are estimated usinglinear regression.

Results of the above in-vitro and in-vivo matrix metalloproteinaseinhibition and TACE inhibition standard pharmacological test proceduresare given in Table I below.

Table I Inhibition of MMP and TACE in-vivo Example MMP#1¹ MMP-9¹ MMP-13¹TACE¹ MMP² 11 172 11 7 >1000 12 933 2 1 190 13 82 15 9  3% 14 108 8 624% 15 139 25 12  7% 16 99 6 3 36% 64%(100) 17 3100 8 16 401 18 152 26627 19 194 2 4 314 20 344 6 9 589 29 200 5 4 30 22 11 467 47 31 225 2 280 32 456 1 1 24 33 1012 1 1 34 301 9 12 20 35 234 4 5 49 36 46 2 1 22681%(50) 37 65 2 1 124 38 100 4 3 336 39 75 2 2 53 40 151 3 4 120 41 1362 2 161 65%(50) 42 5200 874 37 16% 43 43% 71% 63% 20% 44 65% 59% 73%  5%52 45 2.4 1.4 236 74%(100) 60 39 2.9 2.5 160 53%(50) 61 36 2.3 2.3 21472%(50) 62 1236 5.7 23 46% 63 721 6.8 23 64 913 5.5 19 66 512 0.81 0.275%(25) 67 96 3.0 2.4 138 ± 11 68 96 3.0 2.4 115 ± 5  80%(50) 86 131 6.910.0 118 ± 6  87 111 8.9 10 147 ± 5  12%(25) 88 643 10.4 18.7 40.5% 89116 0.8 1.1 356 ± 15 6%(25) 90 550 2.3 3.0 535 ± 77 39%(25) 91(HC1) 18051.8 1.1 38.7% 54%(25) 92 60.2% 12.0 6.1 >1644 30%(25) at 10 μM 93 878610.1 3.9 34.9% 49%(25) 94 2548 3.0 3.2 41.6% 12%(25) 1. IC₅₀ nM or %inhibition at 1 μM concentration 2. % inhibition (dose, mg/kg), p.o. vsMMP-13

Based on the results obtained in the standard pharmacological testprocedures described above, the compounds of this invention were shownto be inhibitors of the enzymes MMP-1, MMP-9, MMP-13 and TNF-αconverting enzyme (TACE) and are therefore useful in the treatment ofdisorders such as arthritis, tumor metastasis, tissue ulceration,abnormal wound healing, periodontal disease, graft rejection, insulinresistance, bone disease and HIV infection.

The compounds of this invention are also useful in treating orinhibiting pathological changes mediated by matrix metalloproteinasessuch as atherosclerosis, atherosclerotic plaque formation, reduction ofcoronary thrombosis from atherosclerotic plaque rupture, restenosis,MMP-mediated osteopenias, inflammatory diseases of the central nervoussystem, skin aging, angiogenesis, tumor metastasis, tumor growth,osteoarthritis, rheumatoid arthritis, septic arthritis, cornealulceration, proteinuria, aneurysmal aortic disease, degenerativecartilage loss following traumatic joint injury, demyelinating diseasesof the nervous system, cirrhosis of the liver, glomerular disease of thekidney, premature rupture of fetal membranes, infammatory bowel disease,age related macular degeneration, diabetic retinopathy, proliferativevitreoretinopathy, retinopathy of prematurity, ocular inflammation,keratoconus, Sjogren's syndrome, myopia, ocular tumors, ocularangiogenesis/neovascularization and corneal graft rejection.

Compounds of this invention may be administered neat or with apharmaceutical carrier to a patient in need thereof. The pharmaceuticalcarrier may be solid or liquid.

Applicable solid carriers can include one or more substances which mayalso act as flavoring agents, lubricants, solubilizers, suspendingagents, fillers, glidants, compression aids, binders ortablet-disintegrating agents or an encapsulating material. In powders,the carrier is a finely divided solid which is in admixture with thefinely divided active ingredient. In tablets, the active ingredient ismixed with a carrier having the necessary compression properties insuitable proportions and compacted in the shape and size desired. Thepowders and tablets preferably contain up to 99% of the activeingredient. Suitable solid carriers include, for example, calciumphosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch,gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose,polyvinylpyrrolidine, low melting waxes and ion exchange resins.

Liquid carriers may be used in preparing solutions, suspensions,emulsions, syrups and elixirs. The active ingredient of this inventioncan be dissolved or suspended in a pharmaceutically acceptable liquidcarrier such as water, an organic solvent, a mixture of both orpharmaceutically acceptable oils or fat. The liquid carrier can containother suitable pharmaceutical additives such a solubilizers,emulsifiers, buffers, preservatives, sweeteners, flavoring agents,suspending agents, thickening agents, colors, viscosity regulators,stabilizers or osmo-regulators. Suitable examples of liquid carriers fororal and parenteral administration include water (particularlycontaining additives as above, e.g., cellulose derivatives, preferablesodium carboxymethyl cellulose solution), alcohols (including monohydricalcohols and polyhydric alcohols, e.g., glycols) and their derivatives,and oils (e.g., fractionated coconut oil and arachis oil). Forparenteral administration the carrier can also be an oily ester such asethyl oleate and isopropyl myristate. Sterile liquid carriers are usedin sterile liquid form compositions for parenteral administration.

Liquid pharmaceutical compositions which are sterile solutions orsuspensions can be utilized by, for example, intramuscular,intraperitoneal or subcutaneous injection. Sterile solutions can also beadministered intravenously. Oral administration may be either liquid orsolid composition form.

The compounds of this invention may be administered rectally in the formof a conventional suppository. For administration by intranasal orintrabronchial inhalation or insufflation, the compounds of thisinvention may be formulated into an aqueous or partially aqueoussolution, which can then be utilized in the form of an aerosol. Thecompounds of this invention may also be administered transdermallythrough the use of a transdermal patch containing the active compoundand a carrier that is inert to the active compound, is non-toxic to theskin, and allows delivery of the agent for systemic absorption into theblood stream via the skin. The carrier may take any number of forms suchas creams and ointments, pastes, gels, and occlusive devices. The creamsand ointments may be viscous liquid or semi-solid emulsions of eitherthe oil in water or water in oil type. Pastes comprised of absorptivepowders dispersed in petroleum or hydrophilic petroleum containing theactive ingredient may also be suitable. A variety of occlusive devicesmay be used to release the active ingredient into the blood stream suchas a semipermeable membrane covering a reservoir containing the activeingredient with or without a carrier, or a matrix containing the activeingredient. Other occlusive devices are known in the literature.

The dosage to be used in the treatment of a specific patient suffering aMMP or TACE dependent condition must be subjectively determined by theattending physician. The variables involved include the severity of thedysfunction, and the size, age, and response pattern of the patient.Treatment will generally be initiated with small dosages less than theoptimum dose of the compound. Thereafter the dosage is increased untilthe optimum effect under the circumstances is reached. Precise dosagesfor oral, parenteral, nasal, or intrabronchial administration will bedetermined by the administering physician based on experience with theindividual subject treated and standard medical principles. Projectedoral daily dosages are 2-500 mg/kg, preferred oral daily dosages are2-50 mg/kg, and more preferred oral daily dosages are 5-25 mg/kg.

Preferably the pharmaceutical composition is in unit dosage form, e.g.,as tablets or capsules. In such form, the composition is sub-divided inunit dose containing appropriate quantities of the active ingredient;the unit dosage form can be packaged compositions, for example packedpowders, vials, ampoules, prefilled syringes or sachets containingliquids. The unit dosage form can be, for example, a capsule or tabletitself, or it can be the appropriate number of any such compositions inpackage form.

What is claimed:
 1. A compound having the formula, B wherein B is

P and Q are

provided that when P is

Q is

and vice versa; W and X are each carbon, T and U are selected fromnitrogen and carbon, provided that when T is nitrogen then U is carbon,and when T is carbon, then U is nitrogen; and when T or U is carbon,either may be optionally substituted,

is a phenyl ring optionally mono-, di-, or tri-substituted with R¹; Z isa phenyl, naphthyl, heteroaryl, or heteroaryl fused to phenyl, whereinthe heteroaryl moiety contains of 5-6 ring atoms and 1-3 heteroatomsselected from nitrogen, oxygen, or sulfur; wherein the phenyl, naphthyl,heteroaryl, or phenyl fused heteroaryl moieties may be optionally mono-,di-, or tri-substituted with R¹; R¹ is hydrogen, halogen, alkyl of 1-8carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms,cycloalkyl of 3-6 carbon atoms, (CH₂)_(n)Z, —OR², —CN, —COR²,perfluoroalkyl of 1-4 carbon atoms, —CONR²R³, —S(O)_(x)R² —OPO(OR²)OR³,—PO(OR³)R³, —OC(O)NR²R³, —COOR², —CONR²R³, —SO₂H, —NR²R¹, —NR²COR³,—NR³COOR³, —SO₂NR²R³, —NO₂, —N(R²)SO₂R³, —NR²CONR²R², —NR³C(═NR³)NR²R²,—SO₂NHCOR¹, —CONHSO₂R¹, -tetrazol-5-yl, —SO₂NHCN, —SO₂NHCONR²R¹, or Z; Vis a saturated or partially unsaturated heterocycloalkyl ring of 5-7ring atoms having 1-3 heteroatoms selected from N, O, or S, which may beoptionally mono, or di substituted with R²; R² and R³ are each,independently, hydrogen, alkyl of 1-8 carbon atoms, alkenyl of 2-6carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbonatoms; perfluoroalkyl of 1-4 carbon atoms, Z or V; R⁴ is alkyl of 1-8carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms,cycloalkyl of 3-6 carbon atoms; perfluoroalkyl of 1-4 carbon atoms, Z orV; R⁵ is hydrogen, alkyl of 1-8 carbon atoms, alkenyl of 2-6 carbonatoms, alkynyl of 2-6 carbon atoms, Z, or V; n=1-6; x=0-2; or apharmaceutically acceptable salt thereof.
 2. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundhaving the formula: B wherein B is

P is

Q is

and vice versa; W and X are each carbon, T and U are selected fromnitrogen and carbon, provided that when T is nitrogen then U is carbon,and when T is carbon, then U is nitrogen; and when T or U is carbon,either may be optionally substituted,

is a phenyl ring optionally mono-, di-, or tri-substituted with R¹; Z isa phenyl, naphthyl, heteroaryl, or heteroaryl fused to phenyl, whereinthe heteroaryl moiety contains of 5-6 ring atoms and 1-3 heteroatomsselected from nitrogen, oxygen, or sulfur; wherein the phenyl, naphthyl,heteroaryl, or phenyl fused heteroaryl moieties may be optionally mono-,di-, or tri-substituted with R¹; R¹ is hydrogen, halogen, alkyl of 1-8carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms,cyclocalkyl of 3-6 carbon atoms, —(CH₂)_(n)Z, —OR², —CN, —COR²,perfluoroalkyl of 1-4 carbon atoms, —CONR¹R³, —S(O)_(x)R² —OPO(OR²)OR³,—PO(OR²)R³, —OC(O)NR²R¹, —COOR¹, CONR¹R³, —SO₃H, —NR²R³, —NR²COR³,—NR²COOR³, SO₂NR²R³, —NO₂, —N(R²)SO₂R¹, —NR²CONR²R³, —NR¹C(—NR³)NR²R³,SO₂NHCOR⁴, —CONHSO₂R⁴, -tetrazol-5-yl, —SO₂NHCN, —SO₂NHCONR²R³, or Z; Vis a saturated or partially unsaturated heterocycloalkyl ring of 5-7ring atoms having 1-3 heteroatoms selected from N, O, or S, which may beoptionally mono-, or di-substituted with R¹; R² and R³ are each,independently, hydrogen, alkyl of 1-8 carbon atoms, alkenyl of 2-6carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbonatoms; perfluoroalkyl of 1-4 carbon atoms, Z or V; R⁴ is alkyl of 1-8carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms,cycloalkyl of 3-6 carbon atoms; perfluoroalkyl of 1-4 carbon atoms, Z orV; R⁵ is hydrogen, alkyl of 1-8 carbon atoms, alkenyl of 2-6 carbonatoms, alkynyl of 2-6 carbon atoms, Z, or V; n=1-6; x=0-2; or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier or diluent.
 3. The compound according to claim 1which is selected from the group consisting of:4-[Benzyl-(4-methoxy-benzenesulfonyl)-amino]-7-trifluoromethyl-quinoline-3-carboxylicacid hydroxyamide,4-[Benzyl-(4-methoxy-benzenesulfonyl)-amino]-8-trifluoromethyl-quinoline-3-carboxylicacid hydroxyamide,4-[Benzyl-(4-methoxy-benzenesulfonyl)-amino]-6-bromo-quinoline-3-carboxylicacid hydroxyamide,4-[Benzyl-(4-methoxy-benzenesulfonyl)-amino]-7-bromo-quinoline-3-carboxylicacid hydroxyamide,4-[Benzyl-(4-methoxy-benzenesulfonyl)-amino]-6-trifluoromethyl-quinoline-3-carboxylicacid hydroxyamide,4-[(4-methoxybenzenesulfonyl)-pyridin-3-ylmethylamino]-7-trifluoromethyl-quinoline-3-carboxylicacid hydroxyamide,4-[Benzyl-(4-methoxybenzenesulfonyl)-amino]-8-t-butyl-quinoline-3-carboxylicacid hydroxyamide,4-[Benzyl-(4-methoxybenzenesulfonyl)-amino]-8-methyl-quinoline-3-carboxylicacid hydroxyamide,8-Ethyl-4-[benzyl-(4-methoxybenzenesulfonyl)-amino]-quinoline-3-carboxylicacid hydroxyamide,4-[Benzyl-(4-methoxybenzenesulfonyl)-amino]-8-(1-methylethyl)-quinoline-3-carboxylicacid hydroxyamide,4-[Ethyl-(4-methoxy-benzenesulfonyl)-amino]-8-vinyl-quinoline-3-carboxylicacid hydroxyamide,4-[Benzyl-(4-methoxy-benzenesulfonyl)-amino]-6-nitro-quinoline-3-carboxylicacid hydroxyamide,4-[Methyl-(4-methoxy-benzenesulfonyl)-amino]-8-bromo-quinoline-3-carboxylicacid hydroxyamide,4-{Methyl-[4-(pyridin-4-yloxy)-benzenesulfonyl]-amino}-6-iodo-quinoline-3-carboxylicacid hydroxyamide,4-{Methyl-(4-(pyridin-4-yloxy)-benzenesulfonyl]-amino}-6-iodo-quinoline-3-carboxylicacid hydroxyamide hydrochloride,4-[Ethyl-(4-methoxy-benzenesulfonyl)-amino]-6-phenylethynyl-quinoline-3-carboxylicacid hydroxyamide,4-[Methyl-(4-methoxy-benzenesulfonyl)-amino]-6-phenylethyl-quinoline-3-carboxylicacid hydroxyamide,4-[(4-Methoxy-benzenesulfonyl)-pyridin-3-ylmethyl-amino]-8-methoxy-quinoline-3-carboxylicacid hydroxyamide,4-[(4-Methoxy-benzenesulfonyl)-pyridin-3-ylmethyl-amino]-8-bromo-quinoline-3-carboxylicacid hydroxyamide, 4-[(4-methoxy-benzenesulfonyl)-pyridin-3-ylmethylamino]-8-Benzyl-quinoline-3-carboxylic acid hydroxyamide,4-[(4-Methoxy-benzenesulfonyl)-pyridin-3-ylmethyl-amino]-8-iodo-quinoline-3-carboxylicacid hydroxyamide,4-[(4-Methoxy-benzenesulfonyl)-pyridin-3-ylmethyl-amino]-8-phenyl-quinoline-3-carboxylicacid hydroxyamide,4-[(4-Methoxy-benzenesulfonyl)-pyridin-3-ylmethyl-amino]-8-thiophen-2-yl-quinoline-3-carboxylicacid hydroxyamide,4-[(Biphenyl-4-sulfonyl)-pyridin-3-ylmethyl-amino]-7-trifluoromethyl-quinoline-3-carboxylicacid hydroxyamide,4-[(Octane-1-sulfonyl)-pyridin-3-ylmethyl-amino]-7-trifluoromethyl-quinoline-3-carboxylicacid hydroxyamide,4-[Pyridin-3-ylmethyl-(toluene-4-sulfonyl)-amino]-7-trifluoromethyl-quinoline-3-carboxylicacid hydroxyamide, or a pharmaceutically acceptable salt thereof.
 4. Thecompound according to claim 1, wherein P is

and Q is

is phenyl, optionally mono-, di-, or tri-substituted with R¹; or apharmaceutically acceptable salt thereof.